WO2004080381A2 - Impregnated powder improving bioavailability and/or solubility and method of production - Google Patents

Impregnated powder improving bioavailability and/or solubility and method of production Download PDF

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Publication number
WO2004080381A2
WO2004080381A2 PCT/FR2004/000541 FR2004000541W WO2004080381A2 WO 2004080381 A2 WO2004080381 A2 WO 2004080381A2 FR 2004000541 W FR2004000541 W FR 2004000541W WO 2004080381 A2 WO2004080381 A2 WO 2004080381A2
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WO
WIPO (PCT)
Prior art keywords
impregnated
powder
tablets
liquid medium
impregnated powder
Prior art date
Application number
PCT/FR2004/000541
Other languages
French (fr)
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WO2004080381A3 (en
Inventor
Jérôme BESSE
Lawrence Besse
Myriam Alphonse
Original Assignee
Sarl Galenix Innovations
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sarl Galenix Innovations filed Critical Sarl Galenix Innovations
Priority to MXPA05009440A priority Critical patent/MXPA05009440A/en
Priority to AU2004218859A priority patent/AU2004218859B2/en
Priority to US10/547,797 priority patent/US7569274B2/en
Priority to BRPI0408065-3A priority patent/BRPI0408065A/en
Priority to JP2006505704A priority patent/JP4901469B2/en
Priority to EP04717669A priority patent/EP1603538A2/en
Priority to CA2518200A priority patent/CA2518200C/en
Publication of WO2004080381A2 publication Critical patent/WO2004080381A2/en
Publication of WO2004080381A3 publication Critical patent/WO2004080381A3/en
Priority to NO20054562A priority patent/NO20054562L/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991—Coated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991—Coated
    • Y10T428/2993—Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991—Coated
    • Y10T428/2993—Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
    • Y10T428/2995—Silane, siloxane or silicone coating
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991—Coated
    • Y10T428/2993—Silicic or refractory material containing [e.g., tungsten oxide, glass, cement, etc.]
    • Y10T428/2996—Glass particles or spheres
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2991—Coated
    • Y10T428/2998—Coated including synthetic resin or polymer

Definitions

  • Impregnated powder improving bioavailability and / or solubility and method of making
  • the present invention relates to a process for the manufacture of an impregnated powder which increases the bioavailability and / or the solubilization of one or more active principle (s) or facilitates its mode of administration, which is inexpensive to manufacture and easy to implement.
  • the active principle (s) can belong to the pharmaceutical, parapharmaceutical, cosmetic, personal hygiene of food supplements or agri-food, liposoluble and / or water-soluble fields.
  • This powder is impregnated with a liquid based on one or more active principle (s). This liquid can be in the form of a solution and a dispersed system.
  • Bioavailability corresponds to the quantity of active ingredient administered which reaches the systemic circulation. The effectiveness of an active ingredient depends on its bioavailability.
  • active ingredients suffer from low bioavailability orally. Before reaching the vena cava, an active ingredient is transported through the gastrointestinal tract and crosses the intestinal wall and the liver. It is in the liver that the active ingredients can be metabolized in an inactive form and undergo the first pass liver effect before reaching the systemic circulation. This first pass liver effect is responsible for the low oral bioavailability of most of the active ingredients.
  • the short residence time in the gastrointestinal tract can also cause poor bioavailability. If the active ingredient does not dissolve quickly or cannot penetrate the epithelial membrane (in the case of a highly ionized or polar active ingredient) absorption may be insufficient. In this case, the bioavailability is variable and very low.
  • Another cause of low bioavailability is attributed to competitive reactions of the absorption phenomenon, namely the formation of complex, hydrolysis by gastric acid or digestive enzymes, conjugation in the intestinal wall, absorption of other active ingredients, metabolism by luminal microflora.
  • the physico-chemical properties of the active ingredients govern its absorption potential, however the properties of the dosage form used largely determine the bioavailability and / or solubility of the active ingredient.
  • the subject of the invention is therefore an impregnated powder increasing the bioavailability and / or the solubility as defined above and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability), of easy and inexpensive manufacture, in contrast to the lyophilization and atomization process generally used in the prior art for the adsorption of fatty substances on a solid support.
  • the invention therefore relates to a powder increasing the bioavailability and / or the solubility of at least one active principle comprising a solid, inert support, in particulate form impregnated with a liquid medium comprising a hydrophobic phase and a hydrophilic phase, at least a surfactant and at least one active principle, characterized in that the active principle (s) is (are) dissolved in one of said hydrophilic or hydrophobic phases and in the form of a suspension in the other of said phases .
  • Another object of the present invention is to provide a process for manufacturing an impregnated powder making it possible to increase the bioavailability and / or the solubility and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability) and in which the integrity of the active principles is preserved.
  • the present invention finally also relates to the use of the impregnated powder increasing the bioavailability and / or the solubility as defined above and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability) for the formulation of various preparations.
  • an impregnated powder increasing the bioavailability and / or the solubility of at least one active principle comprising a solid, inert support, in particulate form impregnated with a liquid medium comprising a hydrophobic phase, and optionally a hydrophilic phase at least one surfactant and at least one active principle dissolved in at least one of said phases, characterized in that the said active principle (s) is (are) also present ( s) in at least one of said phases in the form of a suspension.
  • suspension is meant a dispersion of solid particles in a liquid medium.
  • one of the hydrophobic or hydrophilic phases is in dispersed form in the other of the phases.
  • the liquid medium can also optionally comprise one or more cosurfactant (s), or any other adjuvant necessary for the preparation such as a penetration adjuvant, a mucoadhesive agent, a preservative, a colorant, a flavor, etc. mixtures of these.
  • the phase in which the active principle (s) is (are) dissolved constitutes a saturated solution.
  • the impregnated powder can be obtained by a process comprising the following steps: - obtaining a liquid medium comprising a hydrophobic phase, and optionally a hydrophilic phase, at least a surfactant and at least one active principle dissolved in at least one of said phases and present in at least one of said phases in the form of a suspension; - the mixture d 5 an appropriate amount of the liquid medium and an appropriate amount of an inert solid support in particulate form able to adsorb the liquid medium; and recovering an impregnated powder.
  • the dissolved active ingredient and the active ingredient in suspension form are in separate phases.
  • the liquid medium is obtained by dissolving an amount of active principle (s) in one of said phases, mixing with the phase containing the active principle (s) dissolved in the other of said phases, adding an additional quantity of active principle (s) to the mixture of the two phases to form a suspension of the active principle (s).
  • the liquid medium is obtained by mixing the two phases and by adding a quantity of active principle (s) sufficient to obtain a dissolution of the active principle (s) in the at least one of the phases and a suspension of the active principle (s) in at least the other of the phases.
  • the active principle (s) can be dissolved or dispersed in the hydrophobic phase or in the hydrophilic phase or in both.
  • the process of manufacturing the impregnated powder increasing the bioavailability and / or solubility has the advantage of being easy and inexpensive to implement. All liquid and powder agitation processes known to those skilled in the art can be used.
  • An important advantage of the impregnated powder according to the invention is the increase in the bioavailability and / or solubility of the active principle (s) which are contained therein.
  • the impregnated powder increasing the bioavailability and / or solubility according to the invention can be used as it is or be included in various formulations.
  • another advantage of the impregnated powder increasing the bioavailability and / or solubility of the invention is to allow the realization of various dosage forms, particularly orally administrable or mucosal route (oral, nasal, vaginal 5) or by cutaneous for local or systemic action.
  • the dosage forms are generally dry forms such as bare or dandruff tablets, coated tablets, coated tablets (soluble coating, pH-dependent or independent coating, with gastric, intestinal or other release), matrix tablets, osmotic tablets , multilayer tablets, effervescent tablets, double-core tablets, floating tablets, gastric and / or floating forms, mucoadhesive forms, capsules, powders, multiparticulate forms such as granules, coated microgranules (coated , soluble coating, pH-dependent) or not, mucoadhesive, solid sprays.
  • This impregnated powder can also be applied to fabric-type supports (wipe) to be applied to the body surface, etc.
  • the dosage forms obtained can be in any form of packaging.
  • the impregnated powder increasing the bioavailability and / or solubility according to the invention also has the advantage of allowing high contents of active materials.
  • a liquid medium, saturated or unsaturated and dispersed with active materials, is thus obtained.
  • the liquid medium thus obtained can be impregnated on an inert support.
  • FIG. 1 to 4 flow diagrams of the main steps of different methods of manufacturing the impregnated powder increasing the bioavailability and / or solubility according to the invention.
  • Figures 9 and 12 particle size curves of an impregnated powder according to the invention.
  • the hydrophobic phase of the impregnated powder increasing the bioavailability and / or solubility can consist of any non-toxic compounds conventionally used to form an oily phase.
  • the hydrophobic phase can be chosen from vegetable, animal, mineral or synthetic or semi-synthetic oils, mono, di or tri glycerides, fatty alcohols and their derivatives, polyol esters, liquid paraffin, hydrocarbons long chain such as squalane and squalene, tocopherol and its derivatives, aliphatic fatty acids, fatty acid esters, silicone oils, phospholipid compounds and their derivatives, and mixtures of these compounds.
  • the hydrophobic phase includes aliphatic hydrocarbons, aromatic hydrocarbons, phosphatidylcholine, sterols, cholesterol, lecithin.
  • the oils constituting the oily phase can be polar or nonpolar oils.
  • vegetable oils there may be mentioned the refined oils of sunflower, olive, soya, corn, sesame, sweet almond, peanut, rapeseed as well as avocado oils, wheat germ , castor, coconut, etc ...
  • cod liver oil Among animal oils, mention may be made of cod liver oil, shark liver oil and lanolin oil.
  • paraffin oil Among the mineral oils, mention may be made of paraffin oil.
  • aliphatic fatty acids mention may be made of isostearic acid, lauric acid, linoleic acid and oleic acid.
  • fatty esters mention may be made of dibutyl adipate, dibutyl sebacate, diketyl adipate, diethyl sebacate, dihexyl adipate, diisocetyl adipate, diisopropyl, diisopropyl dimerate, diisopropyl sebaçate, diisostearyl adipate, dioctyl adipate, dioctyl sebaçate and dioctyl succinate, branched chain fatty esters such as 2-ethylhexyl isononanoate, 2 - 5 ethylhexyl myristate, 2-ethylhexyl oxystearate, 2-ethylhexyl palmitate, 2-ethylhexyl pelargonate, 2-ethylhexyl stearate, isocetyl isodecanoate, isocet
  • caprilic / capric triglycerides mention may be made of caprilic / capric triglycerides, triisononanoin, triisostearine, trilaurin, trilinoline and triolein.
  • silicone oils mention may be made of volatile or non-volatile polyorganosiloxane, in particular of polydimethylsiloxane oils, such as cyclic polydimethylsiloxane oils having 3 to 6 silicon atoms, for example cyclomethicone, as well as linear polydimethylsiloxanes .
  • the hydrophobic phase represents from 0.1 to
  • the hydrophilic phase of the impregnated powder increasing the bioavailability and / or solubility can be any non-toxic aqueous phase conventionally used by those skilled in the art.
  • the hydrophilic phase can consist of water (distilled or deionized), a hydroalcoholic mixture, in particular a water / alkanol mixture such as ethanol, an aqueous buffered solution, an aqueous saline solution, an aqueous glucose solution. , and a mixture of water-polyethylene glycol, water-propylene glycol and water-glycerol.
  • the aqueous phase represents from 0.1 to 99.9% by weight, preferably 5 to 60% of the total weight of the liquid medium containing active principle (s).
  • the liquid medium containing in principle active ingredient (s) comprises at least one non-toxic surfactant.
  • the surfactant can be non-ionic, anionic, cationic or amphiphilic. This liquid medium may possibly be neutral or negatively charged depending on the functionality sought.
  • Non-ionic surfactants are also well known compounds per se (see in particular in this regard "Handbook of Surfactants” by MR PORTER, Editions Blackie & Son (Glasgow and London), 1991, pp 116-178) and their nature is not, in the context of the present invention, of a critical nature.
  • alcohols can in particular be chosen from (nonlimiting list) alcohols, alpha-diols, alkylphenols or polyethoxylated, polypropoxylated or polyglycerolated fatty acids, having a fatty chain comprising for example 8 to 18 carbon atoms, the number of ethylene oxide or propylene oxide groups which can range in particular from 2 to 50 and the number of glycerol groups which can range in particular from 2 to 30.
  • polyethoxylated fatty amides preferably having from 2 to 30 moles of ethylene oxide, polyglycerolated fatty amides comprising on average 1 to 5 glycerol groups
  • esters of polyoxyethylenated fatty acids sucrose esters, sucroglycerides, lauryl ether and derivatives, polysorbate, sorbitan ester, dioctyl sodium sulfosuccinate, bis-2-ethylhexyl sodium sulfosuccinate and derivatives, all sorbitan derivatives, polyoxyethylenated glycol alkyl ether.
  • anionic surfactants which can be used, alone or in mixtures, in the context of the present invention, mention may be made in particular (non-limiting list) of the salts (in particular alkaline, in particular sodium, ammonium salts , amine salts, amino alcohol salts or alkaline earth (magnesium) salts of the following compounds: alkyl sulfates, alkyl ether sulfates, alkylamidoethersulfates, alkylarylpolyethersulfates, monoglycerides sulfates; alkylsulfonates, alkylphosphates, alkylamidesulfonates, alkylarylsulfonates, ⁇ -olefins paraffme-sulfonates; alkylsulfosuccinates, alkylethersulfosuccinates, alkylamidesulfosuccinates; alkylsulfosuccinamates; alkyls
  • anionic surfactants which can still be used, mention may also be made of the salts of fatty acids such as the salts of oleic, ricinoleic, palmitic, stearic acids, coconut oil or hydrogenated coconut oil acids; acyl-lactylates whose acyl radical contains 8 to 20 carbon atoms.
  • Weakly anionic surfactants can also be used, such as uronic alkyl D galactoside acids and their salts and also the polyoxyalkylenated (C 6 -C 24 ) alkyl ether carboxylic acids, the polyoxyalkylenated (C 6 -C 24 ) aryl ether carboxylic acids, polyoxyalkylenated alkyl (C6-C24) amido ether acids and their salts, in particular those comprising from 2 to 50 ethylene oxide groups, and their mixtures.
  • uronic alkyl D galactoside acids and their salts and also the polyoxyalkylenated (C 6 -C 24 ) alkyl ether carboxylic acids, the polyoxyalkylenated (C 6 -C 24 ) aryl ether carboxylic acids, polyoxyalkylenated alkyl (C6-C24) amido ether acids and their salts, in particular those comprising from 2 to 50 ethylene oxide groups, and their mixtures.
  • Anionic surfactants also include: petroleum sulfonate, sulfonated glycerides, alpha sulfonate and soaps.
  • anionic surfactants it is preferred to use according to the invention the salts of alkyl sulphates (for example sodium lauryl sulphate) and of alkyl ether sulphates and their mixtures.
  • alkyl sulphates for example sodium lauryl sulphate
  • alkyl ether sulphates and their mixtures.
  • amphoteric surfactants may in particular be (non-limiting list) derivatives of aliphatic secondary or tertiary amines, in which the aliphatic radical is a linear chain or branched having 8 to 22 carbon atoms and containing at least one water-soluble anionic group (for example carboxylate, sulfonate, sulfate, phosphate or phosphanate); Mention may also be made of (C 8 -C 2 o) alkyl betaines, sulfobetaines, (C 8 -C 2 o) alkyl amidoalkyl (C ⁇ -C 6 ) betaines or (C 8 -C 20 ) alkyl amidoalkyl (C ⁇ -C 6 ) sulfobetaines.
  • Amphoteric surfactants also include phospholipids of natural, modified natural, semi-synthetic, synthetic origin, with grafts (lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phytoglycolipid, lysophosphatide, sphyngomyelin), alkylaminocarboxylic acids
  • Cationic surfactants can be in particular (nonlimiting list) alkylated quaternary ammoniums, alkylamine salts and amine oxides.
  • Cationic surfactants include cetrimide, primary amines, acetates and hydrochloride of fatty amines, quaternary ammonium salts, amides of substituted and derived diamines, amides of diethylenetriamine.
  • the amount of surfactant present is at least 1% by weight relative to the total weight of the liquid medium, generally from 2 to 70% by weight, and preferably from 10 to 60% by weight.
  • the liquid medium also contains at least one co-surfactant.
  • the co-surfactant is a compound whose molecule is generally considerably smaller than that of the surfactant and whose role is to act on the molecular stacking at the interface of the droplets, so that the formation of the liquid medium is energetically favored.
  • alkanols in particular from C 3 to C 6 , glycol ethers, glycol and its derivatives, propylene glycol and its derivatives, lauric esters of propylene glycol , polyglycerol and its derivatives, oleic esters of polyglycerole and ethyldiglycol.
  • Co-surfactants include polyoxylated castor oil, hydrogenated polyoxylated castor oil, polyglyceryls and derivatives, organic acids (oleic acid, naphthalenic acid, resinic acid, diacid alcohols (tartaric acid %), triacids alcohols (citric acid), diacids (malonic acid, maleic acid, succinic acid, adipic acid)) alcohols with hydrophilic and / or lipophilic tendency (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, iso-amyl alcohol , hexanol, heptanol, octanol Among, glycols with a hydrophilic and / or hydrophobic tendency (ethylene glycol, propylene glycol, isopropyiene glycol, butylene glycol, butanediol 2-3, isobutene glycol, butanediol
  • fatty acids and their derivatives lauric, palmitic, oleic, stearic acid
  • polyols glycerol, trimethylolpropane, pentane triol 2-3-4
  • amines and polyamines and their derivatives dimethylamine, ethylene diamine, diet hylene triamine, triethylene tretramine, tetra-ethylene pentamine Certainly, amino alcohols (ethanolamine, diethanolamine, triethanolamine, diethyl amino ethanol .
  • the co-surfactant when used, generally represents from 0.01 to 60% by weight of the total weight of the liquid medium containing at least one active principle.
  • the active material (s) included in the liquid medium can be any active principle having an activity in the pharmaceutical, parapharmaceutical, cosmetic, food or agri-food supplements, in particular in the cosmetic fields and / or therapeutic, preferably therapeutic.
  • These active ingredients can be soluble and / or dispersible in one or other of the components of the liquid medium.
  • the active ingredients can be water-soluble, liposoluble or amphiphilic.
  • the active principles of chemical, natural or biological origin, used according to the invention can be selected from those conventionally used in the following pharmacotherapeutic families: allergology, anesthesia / resuscitation, oncology and hematology, cardiology and angiology, contraception and termination of pregnancy, dermatology, endocrinology, gastroenterohepathology, gynecology and obstetrics, immunology and transplantation drugs, infectiology and parasitology, metabolism diabetes and nutrition, neurology / psychiatry, ophthalmology, otolaryngology, pneumology, rheumatology, stomatology, toxicology, urology / nephrology, as well as analgesics / anti-pyretics and antispasmodics, anti-inflammatories, contrast agents used in radiology, hemostats and blood treatment products and derivatives.
  • the active ingredients can be selected from the group consisting of active ingredients passing through the mucosal barrier and reaching the systemic circulation, such as cyproterone acetate, ⁇ -4-androstenedione, 3-keto-desogestrel, desogestrel. .
  • ⁇ -3 adrenergic agonist the ⁇ -3 adrenergic agonist, growth hormone, oxybutinin, buprenorphine, pergolide, nestorone, 7 ⁇ -methyl-19-nortesterone, mecamylamine, salbutamol, selegiline, buspirone, ketotifen, lidocaine, ketorolac, eptazocin, insulin, interferon ⁇ , prostaglandins, 5-aminolevulinic acid, benzodiazepine alprozolam, diclofenac, fenoprofen , flubiprofen, ketoprofen, methylphenidate, miconazole, piroxicam, buprenorphine, alprozolam, dexmedetomidine, prazosin (adrenergic antagonist), alprostadil, tulobuterol ( ⁇ adrenergic agonist) 9 thinylestradin + norelgestol nororostoline + nore
  • Esomeprazole Esomeprazole
  • Melagatran in case of thrombosis
  • Rosuvastatin Ezetimide
  • Pitavastatin hyperlipidemia
  • Mitiglinide type II diabetes
  • Cilomilast Viozan
  • Omapatrilat hypertensive
  • Orzel oncology
  • Caspofongin acetate Voriconazole (infections)
  • new COX inhibitors such as Etoricoxib (inflammation), Valdecoxib (arthritis) and Parecoxib
  • Substance P antagonist depression
  • Darifenacine urology
  • Eletriptan migraine
  • Alosetron Tegaserod
  • Capravirine HAV
  • vitamin A for example isotretinoin, coenzyme Q10
  • antivirals for example acyclovir
  • analgesics for example indometacin, naproxen
  • antiulcers e.g. omeprazole, lansoprazole
  • antisporiasics e.g. Cyclosporine
  • antibiotics cefaclor, amoxicillin, cloxaciline
  • sex hormones antiestrogens, e.g. raloxifene; estrogens, e.g.
  • the active ingredients can also be chosen from those conventionally used in cosmetics, parapharmacy and for food supplements.
  • the contents of these active ingredients are those conventionally used in the fields considered.
  • cosmetic and parapharmaceutical active agents there may be mentioned emollients, humectants, pigments and dyes, anti-wrinkle agents (retinol), anti-fungal agents, anti-acne agents, softeners, perfumes and vitamins.
  • vitamins A, B, E, C, Bl, B2, B3, B6, B9, B12, B8H, B5 .
  • minerals calcium, phosphorus, iron, magnesium, zinc, iodine ...)
  • carotenoids alpha-carotene, beta-carotene, gamma cartene, lutein, zeaxanthin, cryptoxanthin, lycopene ...)
  • phytoestrogens isoflavones (genistein, diadzein, biochanin A , formononetin ...), lignans (enterolactone, enterodiol %), coumestanes (coumestrol)), plant extracts (fennel, heather, blackcurrant, grape seed extract, fucus, ginjseng, green coffee, ginger. ..), oils (evening primrose, wheat germ, borage, pumpkin seeds ...), clays (diosm
  • the content of active material (s) in the impregnated powder increasing the bioavailability and / or the solubility according to the invention is from 0.001 to 70% by weight, preferably from 0.5 to 60% by weight, relative to the total weight of the liquid medium, depending on the nature of the active material.
  • the liquid medium can also contain a penetration adjuvant or a mixture of adjuvants, intended to promote the passage of the active molecules through the membrane concerned.
  • a penetration adjuvant or a mixture of adjuvants, intended to promote the passage of the active molecules through the membrane concerned.
  • the penetration adjuvants mention may be made of the group consisting of esters of aliphatic fatty acids such as isopropyl myristate, fatty acids such as oleic acid; alcohols or polyols such as ethanol, propylene glycol and polyethylene glycol; components of essential oils and terpene derivatives (such as eugenol, geraniol, nerol, eucalyptol, menthol); preferably nonionic surfactants, such as polyoxyethylene sorbitan (fatty acid ester), polyoxyethylene alkyl ether, polyoxyethylene derived from castor oil as well as their mixtures; moisturizers such as glycerin, urea; kerato
  • the liquid medium can also comprise an adhesive agent (mucous membrane, skin), so as to finally obtain an impregnated powder increasing the bioavailability and / or the solubility.
  • adhesive agents mention may be made of carbomers, polyoxyethylenes, methylcelluloses, carboxymethylcelluloses, sodium carboxymethylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses, polyvinylpyrrolidone, polyvinyl alcohol, polyisobutylene, polyisobutylene xanthan, Carob gum, chitosan, polycarboxylates, acrylic / methacrylic acid copolymers, acrylic acid / acrylamide copolymers, acrylic acid / methylmethacrylate copolymers, acrylic acid / polyethylene glycol copolymers, polyacrylic acid / butyl acrylate copolymers , 2-hydroxyethylmethacrylate (HEMA), the compound sold under the name CYDOT ®
  • the amount of adhesive agents present in the liquid medium represents from 0.01 to 70% by weight of the total weight of the liquid medium.
  • thermoreversible polymers such as the compounds marketed under the names LUTROL ® ® xyloglucan and, particularly for the mucosal or dermal administration.
  • the powder impregnated according to the invention can gel on contact with the mucosa or the epidermis.
  • these polymers are present in an amount of 0.01 to 70% by weight of the total weight of the liquid medium.
  • the invention also has the advantage of allowing high contents of active principles.
  • the liquid medium generally represents from 1 to 99%, preferably 20 to 90%, better 40 to 90% and even better 50 to 80% of the total weight of the impregnated powder increasing the bioavailability and / or solubility.
  • the inert support in particulate form can be any non-toxic support that is chemically inert with respect to the liquid medium containing the active principle and its constituents, suitable for the intended application and capable of being impregnated with the liquid medium. without damaging its integrity.
  • particulate inert supports Among the particulate inert supports recommended, mention may be made of natural silicas, silica gels, fumed silicas, precipitated silicas, clays, talc, magnesium hydroxide, aluminum hydroxide, magnesium oxide, maltodextrins, cyclodextrins, cellulose derivatives such as cellulose powder and their mixtures.
  • the preferred particulate inert supports are silicas.
  • the silicas can be hydrophilic, hydrophobic, or amphiphilic. Suitable silicas are marketed under the names AEROSIL ®
  • montmorillonites and bentonites.
  • Maltodextrins are marketed under the brand LYCATAB ® . 0
  • the average particle size of the inert particulate supports according to the invention is generally between 0.001 and 300 ⁇ m, preferably between 1 and 100 ⁇ m.
  • the particulate inert support represents from 1 to 90%, preferably 10 to 80%, better 10 to 60%, and better still 20 to 5 50% by weight of the total weight of the impregnated powder increasing the bioavailability and / or solubility.
  • the impregnated powder can also include any other adjuvant necessary for the preparation such as (non-exhaustive list) flavorings, perfumes, essential oils, colorings, 0 antioxidants, preservatives, sweeteners, fillers, etc. or mixture thereof
  • the particle size of the impregnated powder increasing the bioavailability and / or solubility according to the invention varies from 1 ⁇ m to 100 ⁇ m, preferably from 20 to 50 ⁇ m.
  • the impregnated powder increasing the bioavailability and / or solubility according to the invention can be easily produced by proceeding in the following general manner: firstly, a liquid medium containing at least one active principle is obtained in both dissolved and suspension form. The liquid medium o containing at least one active principle is gradually impregnated with stirring on the inert particulate support. After homogenization of the mixture, the formulation is recovered in the form of an impregnated powder increasing the bioavailability and / or the solubility.
  • FIG. 1 to 4 are flow diagrams of the main steps of variant methods of manufacturing the impregnated powder increasing the bioavailability and / or the solubility according to the invention. s Referring to FIG. 1, there is shown the main steps for manufacturing an impregnated powder increasing the bioavailability and / or the solubility according to the invention including a hydrophobic active principle.
  • the hydrophobic active principle is dissolved, with stirring, in this hydrophobic medium.
  • the active principle is solubilized at saturation, but we can consider the 5 case where it is not at saturation.
  • the aqueous medium is introduced with stirring. Obtaining a liquid containing the active principle (s) at saturation or not depending on the case. At this stage, an additional quantity of the hydrophobic active ingredient is added, with stirring, until the desired active ingredient content is obtained. A suspension is thus obtained, in general in a semi-solid creamy and opaque form.
  • FIG. 2 relates to a variant of the method of FIG. 1 which differs from the latter in that the hydrophilic medium is first added with stirring to the hydrophobic medium, then the desired quantity of hydrophobic active principle is added with stirring up to 0 get the suspension. We can therefore obtain the desired amount of active ingredient. As in the previous case, the suspension is then impregnated on the inert support by simple stirring.
  • FIGS. 3 and 4 are similar to those of FIGS. 1 and 2, respectively, but relate to the incorporation of a hydrophilic active principle, and for which the order of preparation and incorporation of the hydrophobic medium and the aqueous medium.
  • the impregnated powder increasing the bioavailability and / or solubility according to the invention can be used for making various presentations, in particular dosage forms which can be administered orally or mucosally, presentations used in the cosmetic industry, food and agrifood supplements in the parapharmaceutical industry.
  • the manufacturing process remains the same as those described above.
  • impregnated powder increasing the bioavailability and / or the solubility can also be used alone as such and in various presentations in (non-limitative list of the invention) sachets, stick-packs, pressurized bottles or not with or without applicators, wipes, etc.
  • the impregnation support selected from inert powders, the dosage form chosen various release profiles are then accessible such as immediate, modified, delayed, bimodal, pulsed release.
  • the impregnated powder increasing the bioavailability of the invention can also be put in the form of capsules, stick packs (and remain in the form of powder), in sachets, in powder sprayers for nasal, buccal or vaginal route in powder sprayers. with special applicator, etc.
  • diluents for example: microcrystalline cellulose, lactose, cellulose powder, dicalcium phosphate, sucrose, starch, bicarbonate, mannitol .
  • lubricants for example magnesium stearate, sodium stearyl fumarate .
  • binders for example: polyvinylpy ⁇ Olidone-vinyl acetate, povidone .
  • disintegrating agent starch and derivatives, sodium glycolate starch, alginate, microcrystalline cellulose, croscarmellose sodium, crosspovidone ?” or other excipients necessary for the production of tablets.
  • the tablets can be obtained by direct compression, by wet granulation, by dry granulation, or any other technique known to those skilled in the art.
  • Example 1_ making rapid release progesterone fease tablet.
  • solution A saturated with active ingredient
  • the sunflower oil solution (Lesieur) is saturated with progesterone.
  • the surfactant / co-surfactant ratio is fixed at 75/25.
  • the co-surfactant is Transcutol ® (Gattefossé), it also plays the role of absorption promoter and promotes passage through the mucosa.
  • a translucent phase is obtained in which progesterone is incorporated so as to saturate the mixture.
  • progesterone is incorporated so as to saturate the mixture.
  • At temperature ambient with mechanical stirring with the Heidolph Bioblock RZR 2051 agitator: 700 rpm for 4 minutes, it is possible to pass the solution to the ultrasonic bath for a few minutes (6 minutes 30 seconds) in order to speed up the process of solubilization of the active ingredient.
  • Progesterone is added to 62.5% by weight of the previous solution, so as to obtain a suspension dosed at 40% in active principle.
  • progesterone is added to solution A with mechanical stirring with the Heidolph Bioblock RZR 2051 agitator, at 700 rpm for 5 minutes.
  • This suspension B which is generally a semi-solid creamy and opaque form, has the following composition:
  • this suspension B is obtained, it is impregnated on silica such as Sipernat ® 50 (Degussa).
  • silica such as Sipernat ® 50 (Degussa).
  • a Zanchetta mixer-granulator-dryer is used for this manipulation.
  • the B progesterone suspension is gradually incorporated into the device to be impregnated on the silica.
  • the impregnated powder increasing the bioavailability and / or the solubility then has the following composition:
  • Dissolution profile of the impregnated powder increasing the bioavailability and / or the solubility above compared to a pharmaceutical form marketed: Utrogestan ®100mg (Besins.
  • the in vitro dissolution test was carried out with a Sotax AT7 dissolutest, with glass dissolution beakers.
  • the dissolution medium used is 1% kleptose.
  • the temperature of the bath is maintained at 37 ° C., and the speed of rotation of the blades is 150 rpm.
  • the assay is carried out online by UV spectrometry.
  • Apparent volume at V0 122 ml.
  • Apparent volume at V10 114 ml o
  • Apparent volume at V500 104 ml
  • the diluent used is a mixture of Vivapur ® 102 (Rettenma ⁇ er) and Encompress ® (Penwest).
  • composition of the tablets is as follows:
  • Example 2 production of an impregnated powder increasing the bioavailability and / or the solubility based on quick-release fenofibrate.
  • the suspension Al is performed based on DC Labrafac ® (Gattefosse), ® Montanox 85 (Seppic), propylene glycol (Copper), and distilled water.
  • the first 3 components are mixed using a Heidolph Bioblock RZR2051 agitator at 700 rpm.
  • the active ingredient is added to the previous mixture, the formulation is passed through ultrasonic baths for 5 minutes. Then mechanical agitation in the Bioblock at 1200 rpm for 45 minutes.
  • the wording is as follows
  • the formulation loaded with fenofibrate is gradually incorporated into the device to be impregnated on silica.
  • the in vitro dissolution test was carried out with a Sotax AT7 dissolutest, with rotating paddles.
  • the dissolution medium used is from SLS to O.IM.
  • the temperature of the bath is maintained at 37 ° C., and the speed of rotation of the blades is 75 rpm.
  • the assay is carried out online by UV spectrometry. The results are shown graphically in Figure 6.
  • the impregnated powder increasing the bioavailability and / or solubility of the invention permits release of active principle much more rapidly than Lipanthyl ® 160mg in the first 10 minutes.
  • Example 3 ⁇ realization cAn impregnated powder attempting bioavailability and / or care! has a quick release 9 acydov! r case.
  • the last 3 components are mixed using a Heidolph Bioblock RZR2051 agitator at 500 rpm.
  • the active ingredient is added to the previous mixture, the formulation is passed through ultrasonic baths for 5 minutes. Then mechanical agitation in the Bioblock at 900 rpm for 20 minutes.
  • the wording is as follows:
  • the formulation loaded with acyclovir is gradually incorporated into the apparatus to be impregnated on the silica.
  • Example 4 Production of rapid release progesterone tablet.
  • Saturated solution of active ingredient, solution A The hydrophobic phase based on sunflower oil (Lesieur) is saturated with progesterone.
  • the surfactant / co-surfactant ratio is fixed at 75/25.
  • a mixture of surfactants is used: Tween® 80 (Seppic) and Montane® 80 (Seppic).
  • the co-surfactant is Transcutol® (Gattefossé), it also plays the role of promoter of absorption and promotes the passage through the gastrointestinal mucosa.
  • Sunflower oil, montane 80, Tween 80 and Transcutol are mixed using a Heidolph Bioblock RZE2051 agitator, at 500 rpm for 6 min, at room temperature. A translucent phase is obtained in which the progesterone is incorporated until saturation, with stirring at 700 rpm for 4 min.
  • the hydrophilic phase (purified water) is added.
  • the whole is homogenized with the Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min.
  • Progesterone is dispersed in solution A, until a suspension dosed at 45.28% in Progesterone is obtained, with stirring at 700 rpm for 5 min using a Heidolph Bioblock RZR 2051 agitator.
  • the suspension obtained is slightly viscous and white.
  • the suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
  • Adsorption is carried out using a Rotolab mixer-granulator, Zan peu.
  • the impregnation parameters are as follows:
  • the dissolution profile of the progesterone-impregnated powder improving bioavailability and solubility is compared to that of the commercial form Utrogestran®.
  • the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
  • the dissolution medium used is a 1% Kleptose solution.
  • the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 150 RPM.
  • the assay is carried out online by UV spectrophotometry.
  • FIG. 7 illustrates a comparison of the dissolution profile (Kleptose 1%, 150 rpm) of the progesterone-based impregnated powder dosed at 100 mg according to the invention with a commercial formulation. After 1 hour, the entire dose is released with the impregnated powder while only 10% of progesterone is released from the commercial form.
  • the mixture is then compressed with an alternative Frogerais tableting machine.
  • the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
  • the dissolution medium used is a 1% Kleptose solution.
  • the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 150 RPM.
  • the assay is carried out online by UV spectrophotometry.
  • FIG. 8 illustrates a comparison of the dissolution profile (Kleptose 1%, 150 rpm, 37 ° C), between, respectively, (i) a powder impregnated according to the invention, (ii) a powder tablet impregnated according to the invention and (iii), a commercial formulation, dosed at 100 mg of progesterone.
  • the tablets based on the impregnated powder release approximately 95% of progesterone while only 10% of progesterone are released from the commercial form.
  • Acyclovir Acyclovir is dissolved in the hydrophilic phase (HCl buffer, pH 2), at 500 rpm for 10 min, at room temperature. Solution A obtained is clear and fluid.
  • the hydrophobic phase (Captex® 300, Abitec), the surfactant (Acconon® CC6, Abitec) and the co-surfactant (Plural oleic, Gattefossé) are mixed for 5 min, at 500 RPM, at room temperature. Solution B obtained is slightly yellowish and fluid.
  • Solution A sutured in Acyclovir and solution B are mixed, 5 min 500 rpm.
  • the mixture C obtained is fluid and slightly yellowish.
  • PAcyclovir The remainder of PAcyclovir is suspended, with stirring 700RPM, for 10 min.
  • Suspension D obtained at 65% Acyclovir is white and creamy.
  • the suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
  • Adsorption is carried out using a Rotolab mixer-granulator, Zanchetta.
  • the dissolution profile of the impregnated powder based on Acyclovir improving the bioavailability and the solubility is compared with that of the commercial form Zovirax®.
  • the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
  • the dissolution medium used is a 0.01 N HCl solution.
  • the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.
  • the assay is carried out online by UV specfrophotometry.
  • the impregnated powder is mixed with a diluent (Vivapur® 12,
  • the mixture is then compressed with an alternative Frogerais tableting machine.
  • the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
  • the dissolution medium used is a 0.01 N HCl solution.
  • the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.
  • the assay is carried out online by UV spectrophotometry.
  • the dissolution profile results are represented in FIG. 11 which illustrates a comparison of the dissolution profiles (HCl 0.0 IN; 100 rpm) (i) of an impregnated powder based on Acyclovir according to the invention , (ii) a tablet made from this impregnated powder and (iii) a commercial formulation called ZOVIRAX® dosed at 200 mg.
  • FIG. 12 illustrates the curve of distribution of size of the particles of this powder.
  • Capryol® 90 (Gattefossé), Acconon® CC6 (Abitec), Transcutol® (Gattefossé) are mixed using a Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min at room temperature.
  • a translucent phase is obtained in which the co-micronized fenofibrate is incorporated until saturation, with stirring at 700 rpm for 10 min.
  • the hydrophilic phase (purified water) is added.
  • the whole is homogenized with the Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min.
  • the suspension B obtained is viscous and white.
  • the suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
  • Adsorption is carried out using a Rotolab mixer-granulator, Zanchetta.
  • Co-micronized fenofibrate improving bioavailability and solubility is compared to that of the commercial form Lipanthyl.
  • the dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
  • the dissolution medium used is a 0.1 M sodium lauryl sulfate solution.
  • the temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.

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Abstract

The invention relates to a powder which improves the bioavailability and/or solubility of at least one active ingredient comprising a solid, inert support impregnated with a liquid medium comprising a hydrophobic phase and a hydrophilic, at least one surfactant and at least one active ingredient, characterized in that the active ingredient(s) is/are dissolved in one of said hydrophilic or hydrophobic phases and is/are in the form of a suspension in the other of said phases. The impregnated powder is used as a basis for various preparations in the pharmaceutical, parapharmaceutical and cosmetics industry, food supplements and agrifood industry.

Description

Poudre imprégnée améliorant la biodisponibilité et/ou la solubilité et procédé de fabrication Impregnated powder improving bioavailability and / or solubility and method of making
La présente invention concerne un procédé de fabrication d'une poudre imprégnée qui augmente la biodisponibilité et/ou la solubilisation d'un ou de plusieurs principe(s) actif(s) ou facilite son mode d'administration, soit peu onéreuse à fabriquer et facile à mettre en œuvre. Le ou les principe(s) actif(s) peut appartenir au domaine pharmaceutique, parapharmaceutique, cosmétique, hygiène corporelle des compléments alimentaires ou en agroalimentaire, liposoluble et/ou hydrosoluble. Cette poudre est imprégnée d'un liquide à base d'un ou plusieurs princiρe(s) actif(s). Ce liquide pouvant se présenter sous la forme d'une solution et d'un système dispersé. La biodisponibilité correspond à la quantité de principe actif administré qui atteint la circulation systémique. L'efficacité d'un principe actif dépend de sa biodisponibilité.The present invention relates to a process for the manufacture of an impregnated powder which increases the bioavailability and / or the solubilization of one or more active principle (s) or facilitates its mode of administration, which is inexpensive to manufacture and easy to implement. The active principle (s) can belong to the pharmaceutical, parapharmaceutical, cosmetic, personal hygiene of food supplements or agri-food, liposoluble and / or water-soluble fields. This powder is impregnated with a liquid based on one or more active principle (s). This liquid can be in the form of a solution and a dispersed system. Bioavailability corresponds to the quantity of active ingredient administered which reaches the systemic circulation. The effectiveness of an active ingredient depends on its bioavailability.
Beaucoup de principes actifs souffrent par voie orale d'une faible biodisponibilité. Avant d'atteindre la veine cave, un principe actif est véhiculé à travers le tractus gastro-intestinal et traverse la paroi intestinale et le foie. C'est au niveau du foie que les principes actifs peuvent être métabolisés sous forme inactive et subissent l'effet de premier passage hépatique avant d'atteindre la circulation systémique. Cet effet de premier passage hépatique est responsable de la faible biodisponibilité orale de la plupart des principes actifs.Many active ingredients suffer from low bioavailability orally. Before reaching the vena cava, an active ingredient is transported through the gastrointestinal tract and crosses the intestinal wall and the liver. It is in the liver that the active ingredients can be metabolized in an inactive form and undergo the first pass liver effect before reaching the systemic circulation. This first pass liver effect is responsible for the low oral bioavailability of most of the active ingredients.
Une autre cause de faible biodisponibilité est la faible solubilité des principes actifs, en particulier peu hydrosolubles. Le processus d'absorption est alors très long ou incomplet menant à des réponses thérapeutiques aléatoires.Another cause of low bioavailability is the low solubility of the active ingredients, in particular poorly water-soluble. The absorption process is then very long or incomplete leading to random therapeutic responses.
Le faible temps de résidence dans le tractus gastro-intestinal peut également causer une faible biodisponibilité. Si le principe actif ne se dissout pas rapidement ou ne peut pas pénétrer la membrane épithéliale (cas d'un principe actif très ionisé ou polaire) le temps d'absorption peut être insuffisant. Dans ce cas, la biodisponibilité est variable et très faible.The short residence time in the gastrointestinal tract can also cause poor bioavailability. If the active ingredient does not dissolve quickly or cannot penetrate the epithelial membrane (in the case of a highly ionized or polar active ingredient) absorption may be insufficient. In this case, the bioavailability is variable and very low.
Une autre cause de faible biodisponibilité est attribuée aux réactions compétitives du phénomène d'absorption, à savoir la formation de complexe, l'hydrolyse par l'acide gastrique ou les enzymes digestives, la conjugaison dans la paroi intestinale, l'absorption d'autres principes actifs, le métabolisme par la microflore luminale.Another cause of low bioavailability is attributed to competitive reactions of the absorption phenomenon, namely the formation of complex, hydrolysis by gastric acid or digestive enzymes, conjugation in the intestinal wall, absorption of other active ingredients, metabolism by luminal microflora.
Pour plus d'informations sur la biodisponibilité, on pourra se référer au Merck Manuel of diagnostic and therapy, section 22, Clinical pharmacology ; chapitre 298.For more information on bioavailability, reference may be made to the Merck Manual of diagnostic and therapy, section 22, Clinical pharmacology; Chapter 298.
Les propriétés physico-chimiques des principes actifs gouvernent son potentiel d'absorption, cependant les propriétés de la forme galénique mise en œuvre déterminent largement la biodisponibilité et/ou solubilité du principe actif. L'invention a donc pour objet une poudre imprégnée augmentant la biodisponibilité et/ou la solubilité telle que définie précédemment et en particulier permettant d'augmenter l'absorption, la solubilité et/ou la protection du principe actif afin de faciliter l'administration de molécules liposolubles et/ou hydrosolubles (généralement à faible biodisponibilité), de fabrication facile et peu onéreuse, contrairement au procédé de lyophilisation et d'atomisation généralement utilisé dans l'art antérieur pour l'adsorption de corps gras sur un support solide.The physico-chemical properties of the active ingredients govern its absorption potential, however the properties of the dosage form used largely determine the bioavailability and / or solubility of the active ingredient. The subject of the invention is therefore an impregnated powder increasing the bioavailability and / or the solubility as defined above and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability), of easy and inexpensive manufacture, in contrast to the lyophilization and atomization process generally used in the prior art for the adsorption of fatty substances on a solid support.
L'invention est donc relative à une poudre augmentant la biodisponibilité et/ou la solubilité d'au moins un principe actif comprenant un support solide, inerte, sous forme particulaire imprégné par un milieu liquide comprenant une phase hydrophobe et une phase hydrophile, au moins un tensioactif et au moins un principe actif, caractérisée en ce que le(s) principe(s) actif(s) est (sont) dissous dans l'une desdites phases hydrophile ou hydrophobe et sous forme de suspension dans l'autre desdites phases.The invention therefore relates to a powder increasing the bioavailability and / or the solubility of at least one active principle comprising a solid, inert support, in particulate form impregnated with a liquid medium comprising a hydrophobic phase and a hydrophilic phase, at least a surfactant and at least one active principle, characterized in that the active principle (s) is (are) dissolved in one of said hydrophilic or hydrophobic phases and in the form of a suspension in the other of said phases .
La présente invention a encore pour objet de fournir un procédé de fabrication d'une poudre imprégnée permettant d'augmenter la biodisponibilité et/ou la solubilité et en particulier permettant d'augmenter l'absorption, la solubilité et/ou la protection du principe actif afin de faciliter l' administration de molécules liposolubles et/ou hydrosolubles (généralement à faible biodisponibilité) et dans laquelle l'intégrité des principes actifs est préservée. La présente invention a enfin aussi pour objet l'utilisation de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité telle que définie précédemment et en particulier permettant d'augmenter l'absorption, la solubilité et/ou la protection du principe actif afin de faciliter l'administration de molécules liposolubles et/ou hydrosolubles (généralement à faible biodisponibilité) pour la formulation de diverses préparations.Another object of the present invention is to provide a process for manufacturing an impregnated powder making it possible to increase the bioavailability and / or the solubility and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability) and in which the integrity of the active principles is preserved. The present invention finally also relates to the use of the impregnated powder increasing the bioavailability and / or the solubility as defined above and in particular making it possible to increase the absorption, the solubility and / or the protection of the active principle in order to facilitate the administration of liposoluble and / or water-soluble molecules (generally with low bioavailability) for the formulation of various preparations.
Les buts ci-dessus sont atteints selon l'invention par une poudre imprégnée augmentant la biodisponibilité et/ou la solubilité d'au moins un principe actif comprenant un support solide, inerte, sous forme particulaire imprégnée par un milieu liquide comprenant une phase hydrophobe, et facultativement une phase hydrophile au moins un tensioactif et au moins un principe actif dissous dans au moins une desdites phases, caractérisée en ce que le(s)dit(s) principe(s) actif(s) est (sont) également présent(s) dans au moins une desdites phases sous forme d'une suspension.The above aims are achieved according to the invention by an impregnated powder increasing the bioavailability and / or the solubility of at least one active principle comprising a solid, inert support, in particulate form impregnated with a liquid medium comprising a hydrophobic phase, and optionally a hydrophilic phase at least one surfactant and at least one active principle dissolved in at least one of said phases, characterized in that the said active principle (s) is (are) also present ( s) in at least one of said phases in the form of a suspension.
Par suspension, selon la présente invention, on entend une dispersion de particules solides dans un milieu liquide.By suspension, according to the present invention, is meant a dispersion of solid particles in a liquid medium.
De préférence, l'une des phases hydrophobe ou hydrophile est sous forme dispersée dans l'autre des phases. Le milieu liquide peut en outre éventuellement comprendre un ou plusieurs cotensioactif(s), ou tout autre adjuvant nécessaire à la préparation tel qu'un adjuvant de pénétration, un agent mucoadhésif, un conservateur, un colorant, un arôme, etc .. ou des mélanges de ceux-ci. De préférence, la phase dans laquelle le (ou les) principe(s) actif(s) est (sont) dissous constitue une solution saturée.Preferably, one of the hydrophobic or hydrophilic phases is in dispersed form in the other of the phases. The liquid medium can also optionally comprise one or more cosurfactant (s), or any other adjuvant necessary for the preparation such as a penetration adjuvant, a mucoadhesive agent, a preservative, a colorant, a flavor, etc. mixtures of these. Preferably, the phase in which the active principle (s) is (are) dissolved constitutes a saturated solution.
La poudre imprégnée peut être obtenue par un procédé comprenant les étapes suivantes : - l'obtention d'un milieu liquide comprenant une phase hydrophobe, et facultativement une phase hydrophile, au moins un tensioactif et au moins un principe actif dissous dans au moins une desdites phases et présent dans au moins une desdites phases sous forme d'une suspension ; - le mélange d5une quantité appropriée du milieu liquide et d'une quantité appropriée d'un support solide inerte sous forme particulaire capable d'adsorber le milieu liquide ; et la récupération d'une poudre imprégnée.The impregnated powder can be obtained by a process comprising the following steps: - obtaining a liquid medium comprising a hydrophobic phase, and optionally a hydrophilic phase, at least a surfactant and at least one active principle dissolved in at least one of said phases and present in at least one of said phases in the form of a suspension; - the mixture d 5 an appropriate amount of the liquid medium and an appropriate amount of an inert solid support in particulate form able to adsorb the liquid medium; and recovering an impregnated powder.
De préférence, le principe actif dissous et le principe actif sous forme de suspension se trouvent dans des phases distinctes. Dans une première réalisation, le milieu liquide est obtenu en solubilisant une quantité de principe(s) actif(s) dans une desdites phases, mélangeant à la phase contenant le(s) principe(s) actif(s) dissous l'autre desdites phases, ajoutant une quantité supplémentaire de principe(s) actif(s) au mélange des deux phases pour former une suspension du (ou des) principe(s) actif(s).Preferably, the dissolved active ingredient and the active ingredient in suspension form are in separate phases. In a first embodiment, the liquid medium is obtained by dissolving an amount of active principle (s) in one of said phases, mixing with the phase containing the active principle (s) dissolved in the other of said phases, adding an additional quantity of active principle (s) to the mixture of the two phases to form a suspension of the active principle (s).
Dans un autre mode de réalisation, le milieu liquide est obtenu en mélangeant les deux phases et en ajoutant une quantité de principe(s) actif(s) suffisante pour obtenir une dissolution du (des) principe(s) actif(s) dans au moins l'une des phases et une suspension du (des) principe(s) actif(s) dans au moins l'autre des phases.In another embodiment, the liquid medium is obtained by mixing the two phases and by adding a quantity of active principle (s) sufficient to obtain a dissolution of the active principle (s) in the at least one of the phases and a suspension of the active principle (s) in at least the other of the phases.
Le (ou les) principe(s) actif(s) peut (peuvent) être solubilisé(s) ou dispersé(s) dans la phase hydrophobe ou dans la phase hydrophile ou dans les deux.The active principle (s) can be dissolved or dispersed in the hydrophobic phase or in the hydrophilic phase or in both.
L'association de tous ces composants permet d'augmenter la biodisponibilité et/ou la solubilité du ou des principe(s) actif(s).The combination of all these components makes it possible to increase the bioavailability and / or the solubility of the active principle (s).
Le procédé de fabrication de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité a pour avantage d'être facile et peu onéreux à mettre en œuvre. Tous les processus d'agitation de liquide et de poudre connus de l'homme du métier sont utilisables. Un avantage important de la poudre imprégnée selon l'invention est l'augmentation de la biodisponibilité et/ou solubilité du ou des principe(s) actif(s) qui y sont contenu(s).The process of manufacturing the impregnated powder increasing the bioavailability and / or solubility has the advantage of being easy and inexpensive to implement. All liquid and powder agitation processes known to those skilled in the art can be used. An important advantage of the impregnated powder according to the invention is the increase in the bioavailability and / or solubility of the active principle (s) which are contained therein.
La poudre imprégnée augmentant la biodisponibilité et/ou solubilité selon l'invention peut être utilisée telle quelle ou être incluse dans diverses formulations. Ainsi, un autre avantage de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité selon l'invention est de permettre la réalisation de formes galéniques variées, en particulier administrables par voie orale ou par voie mucosale (buccale, nasale5 vaginale) ou par voie cutanée en vue d'une action locale ou systémique. Les formes galéniques sont généralement des formes sèches telles que des comprimés nus ou pellicules, des comprimés dragéifiés, des comprimés enrobés (enrobage soluble, enrobage pH- dépendant ou indépendant, à libération gastrique, intestinale ou autre), des comprimés matriciels, des comprimés osmotiques, des comprimés multicouches, des comprimés effervescents, des comprimés double noyau, des comprimés flottants, des formes à résidence gastrique et/ou flottantes, des formes mucoadhésives, des gélules, des poudres, des formes multiparticulaires telles que des granules, microgranules enrobées (dragéifiées, à enrobage soluble, pH-dépendant) ou non, mucoadhésives, des pulvérisats solides. Cette poudre imprégnée peut aussi être appliquée sur des supports de type tissu (lingette) pour être appliquée sur la surface corporelle, etc.. Les formes galéniques obtenues peuvent se présenter sous toute forme de conditionnement.The impregnated powder increasing the bioavailability and / or solubility according to the invention can be used as it is or be included in various formulations. Thus, another advantage of the impregnated powder increasing the bioavailability and / or solubility of the invention is to allow the realization of various dosage forms, particularly orally administrable or mucosal route (oral, nasal, vaginal 5) or by cutaneous for local or systemic action. The dosage forms are generally dry forms such as bare or dandruff tablets, coated tablets, coated tablets (soluble coating, pH-dependent or independent coating, with gastric, intestinal or other release), matrix tablets, osmotic tablets , multilayer tablets, effervescent tablets, double-core tablets, floating tablets, gastric and / or floating forms, mucoadhesive forms, capsules, powders, multiparticulate forms such as granules, coated microgranules (coated , soluble coating, pH-dependent) or not, mucoadhesive, solid sprays. This impregnated powder can also be applied to fabric-type supports (wipe) to be applied to the body surface, etc. The dosage forms obtained can be in any form of packaging.
La poudre imprégnée augmentant la biodisponibilité et/ou solubilité selon l'invention a également pour avantage de permettre des teneurs en matières actives élevées. On obtient ainsi un milieu liquide saturé ou non et dispersé de matières actives. Le milieu liquide ainsi obtenu peut être imprégné sur un support inerte.The impregnated powder increasing the bioavailability and / or solubility according to the invention also has the advantage of allowing high contents of active materials. A liquid medium, saturated or unsaturated and dispersed with active materials, is thus obtained. The liquid medium thus obtained can be impregnated on an inert support.
La suite de la description se réfère aux figures annexées qui représentent, respectivement :The following description refers to the appended figures which represent, respectively:
Figures 1 à 4, des organigrammes des étapes principales de différents procédés de fabrication de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité selon l'invention ; etFigures 1 to 4, flow diagrams of the main steps of different methods of manufacturing the impregnated powder increasing the bioavailability and / or solubility according to the invention; and
Figures 5 à 8, 10, 11 et 13 des profils de dissolution de la poudre imprégnée augmentant la biodisponibité et/ou solubilité selon l'invention en comparaison avec les profils de dissolution de produits commerciaux. Figures 9 et 12, des courbes granulométriques d'une poudre imprégnée selon l'invention.Figures 5 to 8, 10, 11 and 13 of the dissolution profiles of the impregnated powder increasing the bioavailability and / or solubility according to the invention in comparison with the dissolution profiles of commercial products. Figures 9 and 12, particle size curves of an impregnated powder according to the invention.
La phase hydrophobe de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité peut être constituée de tous composés non-toxiques classiquement utilisés pour former une phase huileuse.The hydrophobic phase of the impregnated powder increasing the bioavailability and / or solubility can consist of any non-toxic compounds conventionally used to form an oily phase.
En particulier, la phase hydrophobe peut être choisie parmi les huiles végétales, animales, minérales ou synthétiques ou semi- synthétiques, les mono, di ou tri glycérides, les alcools gras et leurs dérivés, les esters de polyol, la paraffine liquide, les hydrocarbures à longue chaîne tels que le squalane et le squalène, le tocophérol et ses dérivés, les acides gras aliphatiques, les esters d'acides gras, les huiles de silicone, les composés phospholipidiques et leurs dérivés, et les mélanges de ces composés. En particulier, la phase hydrophobe englobe les hydrocarbones aliphatiques, les hydrocarbones aromatiques, phosphatidylcholine, les stérols, cholestérol, lécithine.In particular, the hydrophobic phase can be chosen from vegetable, animal, mineral or synthetic or semi-synthetic oils, mono, di or tri glycerides, fatty alcohols and their derivatives, polyol esters, liquid paraffin, hydrocarbons long chain such as squalane and squalene, tocopherol and its derivatives, aliphatic fatty acids, fatty acid esters, silicone oils, phospholipid compounds and their derivatives, and mixtures of these compounds. In particular, the hydrophobic phase includes aliphatic hydrocarbons, aromatic hydrocarbons, phosphatidylcholine, sterols, cholesterol, lecithin.
Les huiles constituant la phase huileuse peuvent être des huiles polaires ou apolaires. Parmi les huiles végétales, on peut citer les huiles raffinées de tournesol, d'olive, de soja, de maïs, de sésame, d'amande douce, d'arachide, de colza ainsi que les huiles d'avocat, de germes de blé, de ricin, de noix de coco, etc....The oils constituting the oily phase can be polar or nonpolar oils. Among the vegetable oils, there may be mentioned the refined oils of sunflower, olive, soya, corn, sesame, sweet almond, peanut, rapeseed as well as avocado oils, wheat germ , castor, coconut, etc ...
Parmi les huiles animales, on peut citer l'huile de foie de morue, l'huile de foie de requin et l'huile de lanoline.Among animal oils, mention may be made of cod liver oil, shark liver oil and lanolin oil.
Parmi les huiles minérales, on peut citer l'huile de paraffine.Among the mineral oils, mention may be made of paraffin oil.
Parmi les alcools gras, on peut citer l'alcool béhénylique, l'alcool cétylique, l'alcool isocétylique, l'alcool isostéarylique, l'alcool laurylique, le 2-octyl-dodécanol, l'alcool oléylique, l'alcool méristylique et l'alcool stéarylique.Mention may be made, among fatty alcohols, of behenyl alcohol, cetyl alcohol, isocetyl alcohol, isostearyl alcohol, lauryl alcohol, 2-octyl-dodecanol, oleyl alcohol, meristyl alcohol and stearyl alcohol.
Parmi les acides gras aliphatiques, on peut citer l'acide isostéarique, l'acide laurique, l'acide linoléique, l'acide oléique.Among the aliphatic fatty acids, mention may be made of isostearic acid, lauric acid, linoleic acid and oleic acid.
Parmi les esters gras, on peut citer l'adipate de dibutyle, le sébaçate de dibutyle, l'adipate de dicétyle, le sébaçate de diéthyle, l'adipate de dihexyle, l'adipate de diisocétyle, l'adipate de diisopropyle, le dimérate de diisopropyle, le sébaçate de diisopropyle, l'adipate de diisostéaryle, l'adipate de dioctyle, le sébaçate de dioctyle et le succinate de dioctyle, les esters gras à chaînes ramifiées tels que le 2-éthylhexyl isononanoate, le 2- 5 éthylhexyl myristate, le 2-éthylhexyl oxystearate, le 2-éthylhexyl palmitate, le 2-éthylhexyl pélargonate, le 2-éthylhexyl stéarate, l'isocétyl isodécanoate, l'isocétyl palmitate, l'isodécyl isononanpate, l'isononyl isononanoate, l'isopropyl isostéarate, l'isopropyl laurate, l'isopropyl linoléate, l'isopropyl myristate, l'isopropyl oléate, o l'isopropyl palmitate, l'isopropyl stéarate, l'isostearyle isostéarate, l'isostearyle lactate, l'isostearyle néopentanoate, l'isostearyle palmitate, Pisopridécyl isononanoate et le tocophéryl linoléate, les esters d'acides tribasiques tels que le triisocétyle citrate, le triisopropyl trilinoléate, le triisostéaryle trilinoléate, le trilauryl 5 citrate et le trioctyle citrate, les esters gras à chaîne droite tels que le lauryl lactate, le lauryl myristate, le lauryl palmitate, le lauryl stéarate, le méristyl lactate, le myristyl méristate, le myristyl néopentanoate, le myristyl propionate, le myristyl propionate, le myristyl stéarate, l'oléyl érucate, l'oléyl linoléate, l'oléyl myristate, 0 l'oléyl oléate, l'oléyl stéarate, le stéaryl lactate et le stéaryl oléate.Among the fatty esters, mention may be made of dibutyl adipate, dibutyl sebacate, diketyl adipate, diethyl sebacate, dihexyl adipate, diisocetyl adipate, diisopropyl, diisopropyl dimerate, diisopropyl sebaçate, diisostearyl adipate, dioctyl adipate, dioctyl sebaçate and dioctyl succinate, branched chain fatty esters such as 2-ethylhexyl isononanoate, 2 - 5 ethylhexyl myristate, 2-ethylhexyl oxystearate, 2-ethylhexyl palmitate, 2-ethylhexyl pelargonate, 2-ethylhexyl stearate, isocetyl isodecanoate, isocetyl palmitate, isodecyl isononanpon, isononyl isopropyl isostearate, isopropyl laurate, isopropyl linoleate, isopropyl myristate, isopropyl oleate, o isopropyl palmitate, isopropyl stearate, isostearyl isostearate, isostearyl lactate, isostearyl neopentanoate, isostearyle palmitate, Pisopridecyl isononanoate and tocopheryl linoleate, esters of tribasic acids such as triisoketyl citrate, triisopropyl trilinoleate, triisostearyl trilinoleate, trilauryl 5 citrate and tri octyl citrate, straight chain fatty esters such as lauryl lactate, lauryl myristate, lauryl palmitate, lauryl stearate, meristyl lactate, myristyl meristate, myristyl neopentanoate, myristyl propionate, myristyl propionate, myristyl stearate , oleyl erucate, oleyl linoleate, oleyl myristate, 0 oleyl oleate, oleyl stearate, stearyl lactate and stearyl oleate.
Parmi les triglycérides, on peut citer les triglycérides capriliques/capriques, la triisononanoïne, la triisostéarine, la trilaurine, la trilinoléine et la trioléine.Among the triglycerides, mention may be made of caprilic / capric triglycerides, triisononanoin, triisostearine, trilaurin, trilinoline and triolein.
Parmi les huiles de silicone, on peut citer les huiles de 5 polyorganosiloxane, en particulier de polydiméthylsiloxane, volatiles ou non volatiles, telles que les huiles de polydiméthylsiloxane cycliques ayant 3 à 6 atomes de silicium, par exemple la cyclométhicone, ainsi que les polydiméthylsiloxanes linéaires. 0 Généralement, la phase hydrophobe représente de 0,1 àAmong the silicone oils, mention may be made of volatile or non-volatile polyorganosiloxane, in particular of polydimethylsiloxane oils, such as cyclic polydimethylsiloxane oils having 3 to 6 silicon atoms, for example cyclomethicone, as well as linear polydimethylsiloxanes . 0 Generally, the hydrophobic phase represents from 0.1 to
99.9% en poids préférentiellement 5 à 60% par rapport au poids total du milieu liquide contenant le ou les principe(s) actif(s).99.9% by weight preferably 5 to 60% relative to the total weight of the liquid medium containing the active principle (s).
La phase hydrophile de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité peut être toute phase aqueuse non s toxique classiquement utilisée par l'homme de métier. Ainsi, la phase hydrophile peut être constituée par de l'eau (distillée ou déionisée), un mélange hydroalcoolique, en particulier un mélange eau/alcanol tel que l'éthanol, une solution aqueuse tamponnée, une solution aqueuse saline, une solution aqueuse glucosée, et un mélange eau-polyéthylène glycol, eau-propylène glycol et eau-glycérol.The hydrophilic phase of the impregnated powder increasing the bioavailability and / or solubility can be any non-toxic aqueous phase conventionally used by those skilled in the art. Thus, the hydrophilic phase can consist of water (distilled or deionized), a hydroalcoholic mixture, in particular a water / alkanol mixture such as ethanol, an aqueous buffered solution, an aqueous saline solution, an aqueous glucose solution. , and a mixture of water-polyethylene glycol, water-propylene glycol and water-glycerol.
Généralement, la phase aqueuse représente de 0,1 à 99.9% en poids préférentiellement 5 à 60 % du poids total du milieu liquide contenant en principe(s) actif(s). Comme indiqué précédemment, le milieu liquide contenant en principe(s) actif(s) comprend au moins un tensioactif non toxique. Le tensioactif peut être non-ionique, anionique, cationique ou amphiphile. Ce milieu liquide peut éventuellement être neutre ou chargé négativement en fonction des fonctionnalités recherchées.Generally, the aqueous phase represents from 0.1 to 99.9% by weight, preferably 5 to 60% of the total weight of the liquid medium containing active principle (s). As indicated above, the liquid medium containing in principle active ingredient (s) comprises at least one non-toxic surfactant. The surfactant can be non-ionic, anionic, cationic or amphiphilic. This liquid medium may possibly be neutral or negatively charged depending on the functionality sought.
fi) Tensioactiffs non ioniquef s)fi) Nonionic surfactantsf s)
Les agents tensioactifs non ioniques sont, eux aussi, des composés bien connus en soi (voir notamment à cet égard « Handbook of Surfactants » par M.R. PORTER, Editions Blackie & Son (Glasgow and London), 1991, pp 116-178) et leur nature ne revêt pas, dans le cadre de la présente invention, de caractère critique. Ainsi, ils peuvent être notamment choisis parmi (liste non limitative) les alcools, les alpha-diols, les alkylphénols ou les acides gras polyéthoxylés, polypropoxylés ou polyglycérolés, ayant une chaîne grasse comportant par exemple 8 à 18 atomes de carbone, le nombre de groupements oxyde d'éthylène ou oxyde de propylène pouvant aller notamment de 2 à 50 et le nombre de groupements glycérol pouvant aller notamment de 2 à 30. On peut également citer les copolymères d'oxyde d'éthylène et de propylène, les condensats d'oxyde d'éthylène et de propylène sur des alcools gras ; les amides gras polyéthoxylés ayant de préférence de 2 à 30 moles d'oxyde d'éthylène, les amides gras polyglycérolés comportant en moyenne 1 à 5 groupements glycérol et en particulier 1,5 à 4 ; les esters d'acides gras du sorbitan oxyéthylénés ayant de 2 à 30 moles d'oxyde d'éthylène ; les esters d'acides gras de sucrose, les esters d'acides gras du polyéthylèneglycol, les alkylpolyglycosides, les dérivés de N-alkyl glucamine, les oxydes d'aminés tels que les oxydes d'alkyl (C10-C14) aminés ou les oxydes de N-acylaminopropylmorpholine.Non-ionic surfactants are also well known compounds per se (see in particular in this regard "Handbook of Surfactants" by MR PORTER, Editions Blackie & Son (Glasgow and London), 1991, pp 116-178) and their nature is not, in the context of the present invention, of a critical nature. Thus, they can in particular be chosen from (nonlimiting list) alcohols, alpha-diols, alkylphenols or polyethoxylated, polypropoxylated or polyglycerolated fatty acids, having a fatty chain comprising for example 8 to 18 carbon atoms, the number of ethylene oxide or propylene oxide groups which can range in particular from 2 to 50 and the number of glycerol groups which can range in particular from 2 to 30. Mention may also be made of copolymers of ethylene oxide and of propylene, condensates of ethylene and propylene oxide on fatty alcohols; polyethoxylated fatty amides preferably having from 2 to 30 moles of ethylene oxide, polyglycerolated fatty amides comprising on average 1 to 5 glycerol groups and in particular 1.5 to 4; fatty acid esters of sorbitan oxyethylenated having from 2 to 30 moles of ethylene oxide; sucrose fatty acid esters, acid esters polyethylene glycol fatty acids, alkylpolyglycosides, N-alkyl glucamine derivatives, amine oxides such as alkyl (C 10 -C 14 ) amino oxides or N-acylaminopropylmorpholine oxides.
Sont englobés dans les agents tensio-actifs non ioniques les esters d'acides gras -polyoxyéthylénés, les sucroses esters, les sucroglycérides, les lauryl éther et dérivés, polysorbate, ester de sorbitan, dioctyl sodium sulfosuccinate, le bis-2-éthylhexyl sodium sulfosuccinate et dérivés, tous les dérivés du sorbitan, les polyoxyéthylénés glycol alkyl éther.Are included in nonionic surfactants esters of polyoxyethylenated fatty acids, sucrose esters, sucroglycerides, lauryl ether and derivatives, polysorbate, sorbitan ester, dioctyl sodium sulfosuccinate, bis-2-ethylhexyl sodium sulfosuccinate and derivatives, all sorbitan derivatives, polyoxyethylenated glycol alkyl ether.
(iï) Tensioactiffs anioniquefs(ii) Anionic tensioactiffs
Leur nature ne revêt pas, dans le cadre de la présente invention, de caractère véritablement critique.Their nature is not, in the context of the present invention, of a truly critical nature.
Ainsi, à titre d'exemple de tensioactifs anioniques utilisables, seuls ou en mélanges, dans le cadre de la présente invention, on peut citer notamment (liste non limitative) les sels (en particulier sels alcalins, notamment de sodium, sels d'ammonium, sels d'aminés, sels d'aminoalcools ou sels d'alcalinoterreux (de magnésium) des composés suivants les alkylsulfates, les alkyléthersulfates, alkylamidoéthersulfates, alkylarylpolyéthersulfates, monoglycérides sulfates ; les alkylsulfonates, alkylphosphates, alkylamidesulfonates, alkylarylsulfonates, α-oléfine-sulfonates, paraffme-sulfonates ; les alkylsulfosuccinates, les alkyléthersulfosuccinates, les alkylamidesulfosuccinates ; les alkylsulfosuccinamates ; les alkylsulfoacétates ; les alkylétherphosphates ; les acylsarcosinates ; les acyliséthionates et les N-acyltaurates, le radical alkyle ou acyle de tous ces différents composés comportant de préférence de 12 à 20 atomes de carbone, et le radical aryle désignant de préférence un groupement phényle ou benzyle. Parmi les tensioactifs anioniques encore utilisables, on peut également citer les sels d'acides gras tels que les sels des acides oléique, ricinoléique, palmitique, stéarique, les acides d'huile de coprah ou d'huile de coprah hydrogénée ; les acyl-lactylates dont le radical acyle comporte 8 à 20 atomes de carbone. On peut également utiliser des tensioactifs faiblement anioniques, comme les acides d'alkyl D galactoside uroniques et leurs sels ainsi que les acides alkyl (C6-C24) éther carboxyliques polyoxyalkylénés, les acides alkyl (C6-C24) aryl éther carboxyliques polyoxyalkylénées, les acides alkyl (C6-C24) amido éther carboxyliques polyoxyalkylénés et leurs sels, en particulier ceux comportant de 2 à 50 groupements oxyde d'éthylène, et leurs mélanges.Thus, by way of example of anionic surfactants which can be used, alone or in mixtures, in the context of the present invention, mention may be made in particular (non-limiting list) of the salts (in particular alkaline, in particular sodium, ammonium salts , amine salts, amino alcohol salts or alkaline earth (magnesium) salts of the following compounds: alkyl sulfates, alkyl ether sulfates, alkylamidoethersulfates, alkylarylpolyethersulfates, monoglycerides sulfates; alkylsulfonates, alkylphosphates, alkylamidesulfonates, alkylarylsulfonates, α-olefins paraffme-sulfonates; alkylsulfosuccinates, alkylethersulfosuccinates, alkylamidesulfosuccinates; alkylsulfosuccinamates; alkylsulfoacetates; alkyletherphosphates; acylsarcosinates; acylisethionates and N-acyltaurates, preferably alkyl or acyl compounds, alkyl or acyl compounds carbon atoms, and the aryl radical denoting preferably a phenyl or benzyl group. Among the anionic surfactants which can still be used, mention may also be made of the salts of fatty acids such as the salts of oleic, ricinoleic, palmitic, stearic acids, coconut oil or hydrogenated coconut oil acids; acyl-lactylates whose acyl radical contains 8 to 20 carbon atoms. Weakly anionic surfactants can also be used, such as uronic alkyl D galactoside acids and their salts and also the polyoxyalkylenated (C 6 -C 24 ) alkyl ether carboxylic acids, the polyoxyalkylenated (C 6 -C 24 ) aryl ether carboxylic acids, polyoxyalkylenated alkyl (C6-C24) amido ether acids and their salts, in particular those comprising from 2 to 50 ethylene oxide groups, and their mixtures.
Les tensioactifs anioniques englobent aussi : le sulfonate de pétrole, les glycérides sulfonés, l'alpha sulfonate et les savons.Anionic surfactants also include: petroleum sulfonate, sulfonated glycerides, alpha sulfonate and soaps.
Parmi les tensioactifs anioniques, on préfère utiliser selon l'invention les sels d'alkylsulfates (par exemple lauryl sulfate de sodium) et d'alkyléthersulfates et leurs mélanges.Among the anionic surfactants, it is preferred to use according to the invention the salts of alkyl sulphates (for example sodium lauryl sulphate) and of alkyl ether sulphates and their mixtures.
(m) Tensioactififs amphotèrefs(m) amphoteric surfactants
Les agents tensioactifs amphotères, dont la nature ne revêt pas dans le cadre de la présente invention de caractère critique, peuvent être notamment (liste non limitative) des dérivés d'aminés secondaires ou tertiaires aliphatiques, dans lesquels le radical aliphatique est une chaîne linéaire ou ramifiée comportant 8 à 22 atomes de carbone et contenant au moins un groupe anionique hydrosolubilisant (par exemple carboxylate, sulfonate, sulfate, phosphate ou phosphanate) ; on peut citer encore les alkyl (C8-C2o) bétaïnes, les sulfobétaïnes, les alkyl (C8-C2o) amidoalkyl (Cι-C6) bétaïnes ou les alkyl (C8-C20) amidoalkyl (Cι-C6) sulfobétaïnes.The amphoteric surfactants, the nature of which is not critical in the context of the present invention, may in particular be (non-limiting list) derivatives of aliphatic secondary or tertiary amines, in which the aliphatic radical is a linear chain or branched having 8 to 22 carbon atoms and containing at least one water-soluble anionic group (for example carboxylate, sulfonate, sulfate, phosphate or phosphanate); Mention may also be made of (C 8 -C 2 o) alkyl betaines, sulfobetaines, (C 8 -C 2 o) alkyl amidoalkyl (Cι-C 6 ) betaines or (C 8 -C 20 ) alkyl amidoalkyl (Cι -C 6 ) sulfobetaines.
Les tensioactifs amphotères englobent aussi les phospholipides d'origine naturelle, naturelle modifiée, semi-synthétique, synthétique, avec greffages (lécithine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phytoglycolipide, lysophosphatide, sphyngomyéline), les acides alkylaminocarboxyliqueAmphoteric surfactants also include phospholipids of natural, modified natural, semi-synthetic, synthetic origin, with grafts (lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phytoglycolipid, lysophosphatide, sphyngomyelin), alkylaminocarboxylic acids
iv les tensioactifs cationiquesiv cationic surfactants
Les agents tensioactifs cationiques, dont la nature ne revêt pas dans le cadre de la présente invention de caractère critique, peuvent être notamment (liste non limitative) les ammoniums quaternaires alkylés, les sels d'alkylamines et les oxydes d'aminés.Cationic surfactants, the nature of which is not critical in the context of the present invention, can be in particular (nonlimiting list) alkylated quaternary ammoniums, alkylamine salts and amine oxides.
Les tensioactifs cationiques englobent le cetrimide, les aminés primaires, acétates et chrohydrate d'aminés grasses, les sels d'ammonium quaternaire, les amides de diamines substituées et dérivés, les amides de diéthylènetriamine.Cationic surfactants include cetrimide, primary amines, acetates and hydrochloride of fatty amines, quaternary ammonium salts, amides of substituted and derived diamines, amides of diethylenetriamine.
Généralement, la quantité de tensioactif présent est d'au moins 1% en poids par rapport au poids total du milieu liquide, généralement de 2 à 70% en poids, et de préférence de 10 à 60% en poids.Generally, the amount of surfactant present is at least 1% by weight relative to the total weight of the liquid medium, generally from 2 to 70% by weight, and preferably from 10 to 60% by weight.
De préférence, le milieu liquide contient également au moins un co-tensioactif. Le co-tensioactif est un composé dont la molécule est généralement considérablement plus petite que celle du tensioactif et dont le rôle est d'agir sur l'empilement moléculaire à l'interface des gouttelettes, de telle manière que la formation du milieu liquide soit énergétiquement favorisée.Preferably, the liquid medium also contains at least one co-surfactant. The co-surfactant is a compound whose molecule is generally considerably smaller than that of the surfactant and whose role is to act on the molecular stacking at the interface of the droplets, so that the formation of the liquid medium is energetically favored.
Parmi les co-tensioactifs préférés, on peut citer (liste non limitative) les alcanols en particulier de C3 à C6, les éthers de glycol, le glycol et ses dérivés, le propylène glycol et ses dérivés, les esters lauriques du propylène glycol, le polyglycérol et ses dérivés, les esters oléiques du polyglycérole et l'éthyldiglycol.Among the preferred co-surfactants, mention may be made (non-limiting list) of alkanols, in particular from C 3 to C 6 , glycol ethers, glycol and its derivatives, propylene glycol and its derivatives, lauric esters of propylene glycol , polyglycerol and its derivatives, oleic esters of polyglycerole and ethyldiglycol.
Les co-tensioactifs englobent l'huile de ricin polyoxylée, l'huile de ricin polyoxylée hydrogénée, les polyglycéryl et dérivés, acides organiques (acide oléique, acide naphtalénique, acide résinique, les diacides alcools (acide tartrique...), les triacides alcools (acide citrique), les diacides (acide malonique, acide maléique, acide succinique, acide adipique)) les alcools à tendance hydrophile et/ou lipophile (méthanol, éthanol, propanol, isopropanol, butanol, isobutanol, pentanol, alcool iso- amylique, hexanol, heptanol, octanol...), les glycols à tendance hydrophile et/ou hydrophobe (éthylène glycol, propylène glycol, isopropyiène glycol, butylène glycol, butanediol 2-3, isobutène glycol, butanediol 2-4, hexylene glycol...), les acides gras et leurs dérivés (acide laurique, palmitique, oléique, stéarique), les polyols (glycérol, triméthylolpropane, pentane triol 2-3-4), les aminés et polyamines et leur dérivés (diméthylamine, éthylène diamine, diéthylene triamine, triéthylène trétramine, tétra-éthylène pentamine...), les amino-alcools (éthanolamine, diéthanolamine, triéthanolamine, diéthyl amino éthanol...).Co-surfactants include polyoxylated castor oil, hydrogenated polyoxylated castor oil, polyglyceryls and derivatives, organic acids (oleic acid, naphthalenic acid, resinic acid, diacid alcohols (tartaric acid ...), triacids alcohols (citric acid), diacids (malonic acid, maleic acid, succinic acid, adipic acid)) alcohols with hydrophilic and / or lipophilic tendency (methanol, ethanol, propanol, isopropanol, butanol, isobutanol, pentanol, iso-amyl alcohol , hexanol, heptanol, octanol ...), glycols with a hydrophilic and / or hydrophobic tendency (ethylene glycol, propylene glycol, isopropyiene glycol, butylene glycol, butanediol 2-3, isobutene glycol, butanediol 2-4, hexylene glycol .. .), fatty acids and their derivatives (lauric, palmitic, oleic, stearic acid), polyols (glycerol, trimethylolpropane, pentane triol 2-3-4), amines and polyamines and their derivatives (dimethylamine, ethylene diamine, diet hylene triamine, triethylene tretramine, tetra-ethylene pentamine ...), amino alcohols (ethanolamine, diethanolamine, triethanolamine, diethyl amino ethanol ...).
Le co-tensioactif, lorsqu'il est utilisé, représente généralement de 0,01 à 60% en poids du poids total du milieu liquide contenant au moins un principe actif.The co-surfactant, when used, generally represents from 0.01 to 60% by weight of the total weight of the liquid medium containing at least one active principle.
La (ou les) matière(s) active(s) incluse(s) dans le milieu liquide peut être tout principe actif ayant une activité dans les domaines pharmaceutique, parapharmaceutique, cosmétique, des compléments alimentaires ou agroalimentaires, en particulier dans les domaines cosmétique et/ou thérapeutique, de préférence thérapeutique. Ces principes actifs peuvent être solubles et/ou dispersibles dans l'une ou l'autre des composants du milieu liquide. En particulier, les principes actifs peuvent être hydrosolubles, liposolubles ou amphiphiles.The active material (s) included in the liquid medium can be any active principle having an activity in the pharmaceutical, parapharmaceutical, cosmetic, food or agri-food supplements, in particular in the cosmetic fields and / or therapeutic, preferably therapeutic. These active ingredients can be soluble and / or dispersible in one or other of the components of the liquid medium. In particular, the active ingredients can be water-soluble, liposoluble or amphiphilic.
Les principes actifs d'origine chimique, naturelle ou biologique, utilisés selon l'invention peuvent être sélectionnés parmi ceux classiquement utilisés dans les familles pharmacothérapeutiques suivantes : allergologie, anesthésie / réanimation, cancérologie et hématologie, cardiologie et angiologie, contraception et interruption de grossesse, dermatologie, endocrinologie, gastro-entéro-hépathologie, gynécologie et obstétrique, immunologie et médicaments de la transplantation, infectiologie et parasitologie, métabolisme diabète et nutrition, neurologie / psychiatrie, ophtalmologie, oto-rhino-laryngologie, pneumologie, rhumatologie, stomatologie, toxicologie, urologie / néphrologie, ainsi que parmi les antalgiques/ anti-pyrétiques et antispasmodiques, anti-inflammatoires, les produits de contraste utilisés en radiologie, les hémostatiques et les produits de traitement du sang et dérivés.The active principles of chemical, natural or biological origin, used according to the invention can be selected from those conventionally used in the following pharmacotherapeutic families: allergology, anesthesia / resuscitation, oncology and hematology, cardiology and angiology, contraception and termination of pregnancy, dermatology, endocrinology, gastroenterohepathology, gynecology and obstetrics, immunology and transplantation drugs, infectiology and parasitology, metabolism diabetes and nutrition, neurology / psychiatry, ophthalmology, otolaryngology, pneumology, rheumatology, stomatology, toxicology, urology / nephrology, as well as analgesics / anti-pyretics and antispasmodics, anti-inflammatories, contrast agents used in radiology, hemostats and blood treatment products and derivatives.
Avantageusement, les principes actifs peuvent être sélectionnés dans le groupe constitué par les principes actifs passant la barrière mucosale et atteignant la circulation systémique, telles que l'acétate de cyprotérone, la Δ-4-androstènedione, le 3-kéto- désogestrel, le désogestrel. le gestodène, l'estradiol et ses dérivés, l'acétate de norethistérone, la progestérone, la testostérone, la dihydrotestostérone, la trinitrine, le fentanyl, la nitroglycérine, la nicotine (nicotine S(-)), la scopolamine, la clonidine, le dinitrate d'isosorbide, le lévonorgestrel en association avec l'éthinylestradiol ou avec l'estradiol, l'androstanolone, le dipropionate d'alclométasone, le phlorglucinol, la molsidomine, ainsi que leurs associations.Advantageously, the active ingredients can be selected from the group consisting of active ingredients passing through the mucosal barrier and reaching the systemic circulation, such as cyproterone acetate, Δ-4-androstenedione, 3-keto-desogestrel, desogestrel. . gestodene, estradiol and its derivatives, norethisterone acetate, progesterone, testosterone, dihydrotestosterone, trinitrine, fentanyl, nitroglycerin, nicotine (nicotine S (-)), scopolamine, clonidine, isosorbide dinitrate, levonorgestrel in combination with ethinylestradiol or with estradiol, androstanolone, aclometasone dipropionate, phlorglucinol, molsidomine, as well as their combinations.
Ils peuvent également être sélectionnés parmi les principes actifs passant la barrière mucosale et ayant une action localisée telles que : l'acétazolamide, l'acyclovir, l'adapalene, l'alclométhasone dipropionate, l'amcinonide, l'améléine, le bamethan sulfate + escine, la valérate de bétaméthasone, le dipropionate de bétaméthasone, le bufexamac, la caféine, le monohydrate de calcipotriol, le bromure de cétrimonium, le propionate de clobétasol, le crilanomère, la désonide, le dexpanthenol, le diclofenac, le diflucortonole, la valérate, le difluprednate, le chlorhydrate de diphénydramine, le nitrate d'econazole, l'érythromicine, le pivalate de flumétasone, l'acétonide de fluocinolone, la fluocinodine, le fluocortolone, l'hexanoate de fluocortolone, le pivalate de fluocortolone, l 'hydrocortisone, l'acétate d'hydrocortisone, l'ibacitabine, l'ibuprofène, l'imiquimod, le kétoconazole, le kétoprofène, la lidocaine, la métronidazole, le nitrate de miconazole, le minoxidil, le niflumide acide, la penciclovir, le peroxyde de benzoyle, la piroxam, la povidone iodée, la promestriène, la pyrazonibutasone, la roxithromycine, la sulfacétalmide, le triamsinolone, le tazarotène, le trétinoïne et l'isotrétinoïne, le triclocarban, le monophosphate de vidarabine ainsi que leurs associations.They can also be selected from the active ingredients passing the mucosal barrier and having a localized action such as: acetazolamide, acyclovir, adapalene, alclomethasone dipropionate, amcinonide, ameleine, bamethan sulfate + escin, betamethasone valerate, betamethasone dipropionate, bufexamac, caffeine, calcipotriol monohydrate, cetrimonium bromide, clobetasol propionate, crilanomer, desonide, dexpanthenol, diclofenucon, diclofenac , difluprednate, diphenydramine hydrochloride, econazole nitrate, erythromicin, flumetasone pivalate, fluocinolone acetonide, fluocinodine, fluocortolone, fluocortolone hexanoate, fluocortolone pivalate, fluocortolone pivalate , hydrocortisone acetate, ibacitabine, ibuprofen, imiquimod, ketoconazole, ketoprofen, lidocaine, metronidazole, miconazole nitrate, minoxidil, acid niflumide, penciclovir, benzoyl peroxide, piroxam, povidone iodine, promestriene, pyrazonibutasone, roxithromycin, sulfacetalmide, triamsinolone, tazarotene, tretinoin, trotinoin and isotretin vidarabine monophosphate and their combinations.
Ils peuvent également être sélectionnés parmi les principes actifs suivants : l'agoniste β-3 adrénergique, l'hormone de croissance, l'oxybutinine, la buprenorphine, le pergolide, le nestorone, le 7α-méthyl-19-nortestérone, la mécamylamine, le salbutamol, la sélégiline, la buspirone, la kétotifen, la lidocaïne, le kétorolac, l'eptazocine, l'insuline, l'interféron α, les prostaglandines, l'acide 5-aminolévulinique, la benzodiazepine alprozolam, le diclofenac, le fenoprofen, le flubiprofen, le kétoprofen, la méthylphénidate, la miconazole, le piroxicam, la buprenorphine, l'alprozolam, la dexmedetomidine, la prazosin (antagoniste α adrénergique), l'alprostadil, le tulobutérol (agoniste β adrénergique)9 thinylestradiol + norelgestromin, le kétorolac, la physostigmine, le médindolol (agoniste β adrénergique), la rotigotine, (dopamine D2 antagoniste), la thiatolsérine ainsi que leurs associations.They can also be selected from the following active ingredients: the β-3 adrenergic agonist, growth hormone, oxybutinin, buprenorphine, pergolide, nestorone, 7α-methyl-19-nortesterone, mecamylamine, salbutamol, selegiline, buspirone, ketotifen, lidocaine, ketorolac, eptazocin, insulin, interferon α, prostaglandins, 5-aminolevulinic acid, benzodiazepine alprozolam, diclofenac, fenoprofen , flubiprofen, ketoprofen, methylphenidate, miconazole, piroxicam, buprenorphine, alprozolam, dexmedetomidine, prazosin (adrenergic antagonist), alprostadil, tulobuterol (β adrenergic agonist) 9 thinylestradin + norelgestol nororostoline + norelgestoline nororostoline + norelgestoline nor norgestorinol noretinolin + norelgestolin , medindolol (β adrenergic agonist), rotigotine, (dopamine D2 antagonist), thiatolserine as well as their associations.
Ils peuvent aussi être sélectionnés parmi les principes actifs suivants : Esomeprazole, Melagatran (en cas de thrombose), Rosuvastatine, Ezetimide, Pitavastatine (hyperlipidémie), Mitiglinide (diabète de type II), Cilomilast, Viozan (asthme), Aripipazole (psychiatrie), Omapatrilat (hypertenseur), Orzel (cancérologie), Caspofongine acétate, Voriconazole (infections), nouveaux inhibiteurs COX tels que Etoricoxib (inflammation), Valdecoxib (arthrites) et Parecoxib, Substance P antagoniste (dépression), Darifenacine (urologie), Eletriptan (migraine), Alosetron, Tegaserod, Capravirine (HIV) ainsi que leurs associations.They can also be selected from the following active ingredients: Esomeprazole, Melagatran (in case of thrombosis), Rosuvastatin, Ezetimide, Pitavastatin (hyperlipidemia), Mitiglinide (type II diabetes), Cilomilast, Viozan (asthma), Aripipazole (psychiatry), Omapatrilat (hypertensive), Orzel (oncology), Caspofongin acetate, Voriconazole (infections), new COX inhibitors such as Etoricoxib (inflammation), Valdecoxib (arthritis) and Parecoxib, Substance P antagonist (depression), Darifenacine (urology), Eletriptan (migraine ), Alosetron, Tegaserod, Capravirine (HIV) and their associations.
Parmi les principes actifs préférés selon l'invention, on peut citer les dérivés de la vitamine A (par exemple l'isotrétinoïne, coenzyme Q10), les antiviraux (par exemple acyclovir), les antalgiques (par exemple indométacine, naproxène), les antiulcériques (par exemple oméprazole, lansoprazole), les antisporiasiques (par exemple Cyclosporine), les antibiotiques (céfaclor, amoxicilline, cloxaciline), les hormones sexuelles (antiestrogènes, par exemple raloxifène ; estrogènes, par exemple estradiol, hexahydrobenzoate d'estradiol, undécylate d'estradiol, valérate d'estradiol, éthinyl estradiol ; les progestatifs, par exemple énanthate de norethistérone, progestérone ; les androgènes, par exemple propionate de testostérone, cyclohexylmethylcarbonate de testotérone ; et les antiandrogènes, par exemple l'acétate de cyprotérone.Among the active ingredients preferred according to the invention, there may be mentioned derivatives of vitamin A (for example isotretinoin, coenzyme Q10), antivirals (for example acyclovir), analgesics (for example indometacin, naproxen), antiulcers (e.g. omeprazole, lansoprazole), antisporiasics (e.g. Cyclosporine), antibiotics (cefaclor, amoxicillin, cloxaciline), sex hormones (antiestrogens, e.g. raloxifene; estrogens, e.g. estradiol, estradiol hexahydrobenzoate, undecylate) estradiol, estradiol valerate, ethinyl estradiol; progestins, for example norethisterone enanthate, progesterone; androgens, for example testosterone propionate, testosterone cyclohexylmethylcarbonate; and antiandrogens, for example cyproterone acetate.
Les principes actifs peuvent être également choisis parmi ceux classiquement utilisés en cosmétique, parapharmacie et pour les compléments alimentaires. Les teneurs en ces principes actifs sont ceux classiquement utilisés dans les domaines considérés.The active ingredients can also be chosen from those conventionally used in cosmetics, parapharmacy and for food supplements. The contents of these active ingredients are those conventionally used in the fields considered.
Parmi les actifs cosmétiques et parapharmaceutiques, on peut citer les émollients, les humidifiants, les pigments et les colorants, les agents antirides (rétinol), les agents antifongiques, les agents anti-acné, les assouplissants, les parfums et les vitamines.Among the cosmetic and parapharmaceutical active agents, there may be mentioned emollients, humectants, pigments and dyes, anti-wrinkle agents (retinol), anti-fungal agents, anti-acne agents, softeners, perfumes and vitamins.
Parmi les actifs pour compléments alimentaires, on peut citer les vitamines (A, B, E, C, Bl, B2, B3, B6, B9, B12, B8H, B5 ...), les minéraux (calcium, phosphore, fer, magnésium, zinc, iode ...), les caroténoïdes (alpha-carotène, béta-carotène, gamma cartène, lutéine, zéaxanthine, cryptoxanthine, lycopène ...), les phyto-estrogènes (les isoflavones (génistéine, diadzéine, biochanine A, formononétine ...), les lignanes (entérolactone, entérodiol ...), les coumestanes (coumestrol)), les extraits végétaux (fenouil, bruyère, cassis, extrait de pépins de raisin, fucus, ginjseng, café vert, gingembre ...), les huiles (onagre, germe de blé, bourrache, pépins de courge ...), les argiles (diosmestite - montmorillonites ...), les ferments et levures, ou encore la pectine de pomme.Among the active ingredients for food supplements, there may be mentioned vitamins (A, B, E, C, Bl, B2, B3, B6, B9, B12, B8H, B5 ...), minerals (calcium, phosphorus, iron, magnesium, zinc, iodine ...), carotenoids (alpha-carotene, beta-carotene, gamma cartene, lutein, zeaxanthin, cryptoxanthin, lycopene ...), phytoestrogens (isoflavones (genistein, diadzein, biochanin A , formononetin ...), lignans (enterolactone, enterodiol ...), coumestanes (coumestrol)), plant extracts (fennel, heather, blackcurrant, grape seed extract, fucus, ginjseng, green coffee, ginger. ..), oils (evening primrose, wheat germ, borage, pumpkin seeds ...), clays (diosmestite - montmorillonites ...), ferments and yeasts, or even apple pectin.
Suivant le principe actif (ou le mélange des principes actifs) sélectionné, plusieurs formulations du milieu liquide sont disponibles selon le profil de libération souhaité.Depending on the active ingredient (or the mixture of active ingredients) selected, several formulations of the liquid medium are available depending on the desired release profile.
Généralement, la teneur en matière(s) active(s) de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité selon l'invention est de 0,001 à 70% en poids, de préférence de 0,5 à 60% en poids, par rapport au poids total du milieu liquide, en fonction de la nature de la matière active.Generally, the content of active material (s) in the impregnated powder increasing the bioavailability and / or the solubility according to the invention is from 0.001 to 70% by weight, preferably from 0.5 to 60% by weight, relative to the total weight of the liquid medium, depending on the nature of the active material.
Le milieu liquide peut également contenir un adjuvant de pénétration ou un mélange d'adjuvants, destinés à favoriser le passage des molécules actives à travers la membrane concernée. Parmi les adjuvants de pénétration, on peut citer le groupe constitué par les esters d'acide gras aliphatiques comme le myristate d'isopropyle, les acides gras comme l'acide oléique ; les alcools ou polyols tels que l'éthanol, le propylène glycol et le polyéthylèneglycol ; les composants des huiles essentielles et dérivés terpéniques (comme l'eugénol, le géraniol, le nérol, l'eucalyptol, le menthol) ; les tensioactifs de préférence non ioniques, tels que le polyoxyéthylène sorbitan (ester d'acide gras), le polyoxyéthylène alkyl éther, le polyoxyéthylène dérivé de l'huile de ricin ainsi que leurs mélanges ; les hydratants comme la glycérine, l'urée ; des kératolytiques comme les alpliahydroxyacides, le 23- lauryl éther, l'aprotinin, l'azote, le chlorure de benzalkonium, le chlorure de cétylpyridinium, le bromure de cétyltriméthylammonium, les cyclodextrines, le sulfate de dextrane, l'acide laurique, la lysophosphatidylcholine, le méthoxysalicylate, le méthyloléate, l'acide oléique, la phosphatidylcholine, le polyoxyhethylene, le polysorbate 80, l'EDTA de sodium, le glycocholate de sodium, le glycodéoxycholate de sodium, le lauryl sulfate de sodium, le salycilate de sodium, le taurocholate de sodium, le taurodéoxycholate de sodium, les sulfoxydes et les alkyl glycosides.The liquid medium can also contain a penetration adjuvant or a mixture of adjuvants, intended to promote the passage of the active molecules through the membrane concerned. Among the penetration adjuvants, mention may be made of the group consisting of esters of aliphatic fatty acids such as isopropyl myristate, fatty acids such as oleic acid; alcohols or polyols such as ethanol, propylene glycol and polyethylene glycol; components of essential oils and terpene derivatives (such as eugenol, geraniol, nerol, eucalyptol, menthol); preferably nonionic surfactants, such as polyoxyethylene sorbitan (fatty acid ester), polyoxyethylene alkyl ether, polyoxyethylene derived from castor oil as well as their mixtures; moisturizers such as glycerin, urea; keratolytics such as alpliahydroxy acids, 23-lauryl ether, aprotinin, nitrogen, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrins, dextran sulfate, lauric acid, lysophosphatidchine , methoxysalicylate, methyloleate, oleic acid, phosphatidylcholine, polyoxyhethylene, polysorbate 80, sodium EDTA, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, sodium salycilate, sodium taurocholate, sodium taurodeoxycholate, sulfoxides and alkyl glycosides.
Le milieu liquide peut également comporter un agent adhésif (muqueuse, peau) , de manière à obtenir au final une poudre imprégnée augmentant la biodisponibilité et/ou la solubilité. Parmi les agents adhésifs, on peut citer les carbomères, les polyoxyéthylénés, les méthylcelluloses, les carboxyméthylcelluloses, les carboxyméthylcelluloses sodiques, les hydroxyéthylcelluloses, les hydroxypropylcelluloses, les hydroxypropylméthylcelluloses, la polyvinylpyrrolidone, l'alcool polyvinylique, le polyisobutylène, le polyisoprène, la gomme de xanthane, la gomme de Caroube, le chitosan, les polycarboxylates, les copolymeres acide acrylique / méthacrylique, les copolymeres acide acrylique / acrylamide, les copolymeres acide acrylique / méthylméthacrylate, les copolymeres acide acrylique / polyéthylène glycol, les copolymeres acide polyacrylique / acrylate de butyle, le 2-hydroxyéthylméthacrylate (HEMA), le composé commercialisé sous le nom CYDOT® par la société 3 M (carbopol associé à du polyisobutylène), la pectine (de basse viscosité), les copolymeres méthylvinyléther / anhydrite maléique, le tragacanthe, le monoéthyléther, le monométhyléther, l'amidon de maïs cireux, le stéaryl fumarate de sodium, l'hyaluronate de sodium, la gomme de guar, l'alginate de sodium, l'amidon, le dextran et ses dérivés, les polymères acrylique, les silicones et dérivés siliconés, les résines de colophane et leurs mélanges.The liquid medium can also comprise an adhesive agent (mucous membrane, skin), so as to finally obtain an impregnated powder increasing the bioavailability and / or the solubility. Among the adhesive agents, mention may be made of carbomers, polyoxyethylenes, methylcelluloses, carboxymethylcelluloses, sodium carboxymethylcelluloses, hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropylmethylcelluloses, polyvinylpyrrolidone, polyvinyl alcohol, polyisobutylene, polyisobutylene xanthan, Carob gum, chitosan, polycarboxylates, acrylic / methacrylic acid copolymers, acrylic acid / acrylamide copolymers, acrylic acid / methylmethacrylate copolymers, acrylic acid / polyethylene glycol copolymers, polyacrylic acid / butyl acrylate copolymers , 2-hydroxyethylmethacrylate (HEMA), the compound sold under the name CYDOT ® by the company 3M (carbopol associated with polyisobutylene), pectin (low viscosity), the methyl vinyl ether / anhydrous maleic, tragacanth, monoethyl , monomethyl ther, the waxy corn starch, stearyl sodium fumarate, sodium hyaluronate, guar gum, sodium alginate, starch, dextran and its derivatives, acrylic polymers, silicones and silicone derivatives, rosin resins and their mixtures.
En général, la quantité d'agents adhésifs présents dans le milieu liquide représente de 0,01 à 70% en poids du poids total du milieu liquide.In general, the amount of adhesive agents present in the liquid medium represents from 0.01 to 70% by weight of the total weight of the liquid medium.
Il peut également être intéressant d'introduire dans le milieu liquide un ou plusieurs polymères thermoréversibles tels que les composés commercialisés sous les noms LUTROL® et XYLOGLUCAN®, en particulier pour l'administration par voie mucosale ou cutanée. Ainsi, la poudre imprégnée selon l'invention peut se gélifier au contact de la muqueuse ou de l'épiderme. En général, ces polymères sont présents à raison de 0,01 à 70% en poids du poids total du milieu liquide. L'invention a également pour avantage de permettre des teneurs élevées en principes actifs.It may also be advantageous to introduce into the liquid medium one or more thermoreversible polymers such as the compounds marketed under the names LUTROL ® ® xyloglucan and, particularly for the mucosal or dermal administration. Thus, the powder impregnated according to the invention can gel on contact with the mucosa or the epidermis. In general, these polymers are present in an amount of 0.01 to 70% by weight of the total weight of the liquid medium. The invention also has the advantage of allowing high contents of active principles.
Le milieu liquide représente généralement de 1 à 99%, de préférence 20 à 90%, mieux 40 à 90% et encore mieux 50 à 80% du poids total de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité.The liquid medium generally represents from 1 to 99%, preferably 20 to 90%, better 40 to 90% and even better 50 to 80% of the total weight of the impregnated powder increasing the bioavailability and / or solubility.
Le support inerte sous forme particulaire, peut être tout support, non toxique, inerte chimiquement vis-à-vis du milieu liquide contenant le principe actif et de ses constituants, convenant pour l'application envisagée et capable d'être imprégné par le milieu liquide sans nuire à son intégrité.The inert support in particulate form can be any non-toxic support that is chemically inert with respect to the liquid medium containing the active principle and its constituents, suitable for the intended application and capable of being impregnated with the liquid medium. without damaging its integrity.
Ceux sont généralement des poudres inertes, non toxiques, ayant un fort pouvoir adsorbant, pouvant adsorber plusieurs fois leur poids en liquide.They are generally inert, non-toxic powders, having a strong adsorbing power, which can adsorb several times their weight in liquid.
Parmi les supports inertes particulaires recommandés, on peut citer des silices naturelles, les gels de silice, les silices fumées, les silices précipitées, les argiles, le talc, Phydroxyde de magnésium, l'hydroxyde d'aluminium, l'oxyde de magnésium, les maltodextrines, les cyclodextrines, des dérivés cellulosiques tels que la poudre de cellulose et leurs mélanges. Les supports inertes particulaires préférés sont les silices. Les silices peuvent être hydrophiles, hydrophobes, ou amphiphiles. Des silices convenables sont commercialisées sous les noms AEROSIL® Among the particulate inert supports recommended, mention may be made of natural silicas, silica gels, fumed silicas, precipitated silicas, clays, talc, magnesium hydroxide, aluminum hydroxide, magnesium oxide, maltodextrins, cyclodextrins, cellulose derivatives such as cellulose powder and their mixtures. The preferred particulate inert supports are silicas. The silicas can be hydrophilic, hydrophobic, or amphiphilic. Suitable silicas are marketed under the names AEROSIL ®
(hydrophile, hydrophobe), AEROPERL ® (hydrophile, hydrophobe), s SYLOÏD® et SIPERNAT® (amphiphile), CAB-O-SIL® .(hydrophilic, hydrophobic), AEROPERL ® (hydrophilic, hydrophobic), s SYLOÏD ® and SIPERNAT ® (amphiphilic), CAB-O-SIL®.
Parmi les argiles, on peut citer les montmorillonites et les bentonites.Among the clays, mention may be made of montmorillonites and bentonites.
Des maltodextrines sont commercialisées sous la marque LYCATAB®. 0 La taille moyenne des particules des supports inertes particulaires selon l'invention est généralement comprise entre 0.001 et 300 μm, préférentiellement entre 1 et 100 μm.Maltodextrins are marketed under the brand LYCATAB ® . 0 The average particle size of the inert particulate supports according to the invention is generally between 0.001 and 300 μm, preferably between 1 and 100 μm.
En général, le support inerte particulaire représente de 1 à 90%, de préférence 10 à 80%, mieux 10 à 60%, et mieux encore 20 à 5 50% en poids du poids total de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité.In general, the particulate inert support represents from 1 to 90%, preferably 10 to 80%, better 10 to 60%, and better still 20 to 5 50% by weight of the total weight of the impregnated powder increasing the bioavailability and / or solubility.
La poudre imprégnée peut également comprendre tout autre adjuvant nécessaire à la préparation tels que (liste non limitative) les arômes, les parfums, les huiles essentielles, des colorants, des 0 antioxydants, des conservateurs, des édulcorants, des charges, etc...ou mélange de ceux-ciThe impregnated powder can also include any other adjuvant necessary for the preparation such as (non-exhaustive list) flavorings, perfumes, essential oils, colorings, 0 antioxidants, preservatives, sweeteners, fillers, etc. or mixture thereof
En général, la taille des particules de la poudre imprégnée augmentant la biodisponibilité et/ou solubilité selon l'invention varie de 1 μm à 100 μm, de préférence de 20 à 50 μm. 5 La poudre imprégnée augmentant la biodisponibilité et/ou solubilité selon l'invention peut être fabriquée facilement en procédant de la manière générale suivante : on commence par réaliser un milieu liquide contenant au moins un principe actif sous forme à la fois dissoute et de suspension. Le milieu liquide o contenant au moins un principe actif est progressivement imprégné sous agitation sur le support inerte particulaire. Après homogénéisation du mélange, on récupère la formulation sous forme d'une poudre imprégnée augmentant la biodisponibilité et/ou la solubilité. Les figures 1 à 4 sont des organigrammes des principales étapes de variantes de procédés de fabrication de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité selon l'invention. s En se référant à la figure 1, on y a représenté les étapes principales de fabrication d'une poudre imprégnée augmentant la biodisponibilité et/ou la solubilité selon l'invention incluant un principe actif hydrophobe.In general, the particle size of the impregnated powder increasing the bioavailability and / or solubility according to the invention varies from 1 μm to 100 μm, preferably from 20 to 50 μm. The impregnated powder increasing the bioavailability and / or solubility according to the invention can be easily produced by proceeding in the following general manner: firstly, a liquid medium containing at least one active principle is obtained in both dissolved and suspension form. The liquid medium o containing at least one active principle is gradually impregnated with stirring on the inert particulate support. After homogenization of the mixture, the formulation is recovered in the form of an impregnated powder increasing the bioavailability and / or the solubility. FIGS. 1 to 4 are flow diagrams of the main steps of variant methods of manufacturing the impregnated powder increasing the bioavailability and / or the solubility according to the invention. s Referring to FIG. 1, there is shown the main steps for manufacturing an impregnated powder increasing the bioavailability and / or the solubility according to the invention including a hydrophobic active principle.
Comme le montre la figure 1, on commence par mélanger tous o les composants à tendance lipophile (le milieu hydrophobe, les tensioactifs et éventuellement cotensioactif), puis on solubilise le principe actif hydrophobe, sous agitation, dans ce milieu hydrophobe. Afin d'avoir le maximum d'activité thermodynamique le principe actif est solubilisé à saturation mais on peut envisager le 5 cas ou il n'est pas à saturation.As shown in FIG. 1, we start by mixing all the components with a lipophilic tendency (the hydrophobic medium, the surfactants and optionally co-surfactants), then the hydrophobic active principle is dissolved, with stirring, in this hydrophobic medium. In order to have the maximum thermodynamic activity, the active principle is solubilized at saturation, but we can consider the 5 case where it is not at saturation.
Après solubilisation du principe actif hydrophobe, on introduit sous agitation le milieu aqueux. Obtention d'un liquide contenant le ou les principe(s) actif(s) à saturation ou non suivant le cas. A ce stade, on rajoute, sous agitation, une quantité supplémentaire du 0 principe actif hydrophobe jusqu'à obtention de la teneur voulue en principe actif. On obtient ainsi une suspension, en général sous forme semi-solide crémeuse et opaque.After solubilization of the hydrophobic active principle, the aqueous medium is introduced with stirring. Obtaining a liquid containing the active principle (s) at saturation or not depending on the case. At this stage, an additional quantity of the hydrophobic active ingredient is added, with stirring, until the desired active ingredient content is obtained. A suspension is thus obtained, in general in a semi-solid creamy and opaque form.
Cette suspension est alors imprégnée sur le support solide inerte sous simple agitation. On obtient ainsi la poudre imprégnée s augmentant la biodisponibilité.This suspension is then impregnated on the inert solid support with simple stirring. The impregnated powder is thus obtained, increasing the bioavailability.
La figure 2 concerne une variante du procédé de la figure 1 qui diffère de ce dernier en ce que le milieu hydrophile est d'abord ajouté sous agitation au milieu hydrophobe, puis on ajoute sous agitation la quantité voulue de principe actif hydrophobe jusqu'à 0 obtenir la suspension. On peut donc obtenir la quantité de principe actif désirée. Comme dans le cas de figure précédent, la suspension est alors imprégnée sur le support inerte par simple agitation.FIG. 2 relates to a variant of the method of FIG. 1 which differs from the latter in that the hydrophilic medium is first added with stirring to the hydrophobic medium, then the desired quantity of hydrophobic active principle is added with stirring up to 0 get the suspension. We can therefore obtain the desired amount of active ingredient. As in the previous case, the suspension is then impregnated on the inert support by simple stirring.
Les procédés des figures 3 et 4 sont semblables à ceux des figures 1 et 2, respectivement, mais concernent l'incorporation d'un 5 principe actif hydrophile, et pour lesquels on a interverti l'ordre de préparation et d'incorporation du milieu hydrophobe et du milieu aqueux.The methods of FIGS. 3 and 4 are similar to those of FIGS. 1 and 2, respectively, but relate to the incorporation of a hydrophilic active principle, and for which the order of preparation and incorporation of the hydrophobic medium and the aqueous medium.
Comme indiqué précédemment, la poudre imprégnée augmentant la biodisponibilité et/ou solubilité selon l'invention peut être utilisée pour réaliser des présentations variées, en particulier des formes galéniques administrables par voie orale ou par voie mucosale, des présentations utilisées dans l'industrie cosmétique, des compléments alimentaires, agroalimentaire, dans l'industrie parapharmaceutique. Dans le cas d'un principe actif amphiphile, le procédé de fabrication reste le même que ceux décrits précédemment.As indicated previously, the impregnated powder increasing the bioavailability and / or solubility according to the invention can be used for making various presentations, in particular dosage forms which can be administered orally or mucosally, presentations used in the cosmetic industry, food and agrifood supplements in the parapharmaceutical industry. In the case of an amphiphilic active principle, the manufacturing process remains the same as those described above.
La poudre imprégnée augmentant la biodisponibilité et/ou la solubilité peut être également utilisée seule en tant que telle et dans diverses présentations dans (liste non limitative de l'invention) des sachets, les stick-packs, des flacons pressurisés ou non avec ou sans applicateurs, des lingettes, etc.The impregnated powder increasing the bioavailability and / or the solubility can also be used alone as such and in various presentations in (non-limitative list of the invention) sachets, stick-packs, pressurized bottles or not with or without applicators, wipes, etc.
Selon la composition du milieu liquide, le support d'imprégnation sélectionné parmi les poudres inertes, la forme galénique choisie, divers profils de libération sont alors accessibles tels que libération immédiate, modifiée, retardée, bimodale, puisée.Depending on the composition of the liquid medium, the impregnation support selected from inert powders, the dosage form chosen, various release profiles are then accessible such as immediate, modified, delayed, bimodal, pulsed release.
La poudre imprégnée augmentant la biodisponibilité de l'invention peut également être mise sous forme de gélules, stick packs (et rester sous forme de poudre), en sachets, dans des pulvérisateurs de poudres pour voie nasale, buccale ou vaginale dans des pulvérisateurs de poudres avec applicateur spécial, etc.The impregnated powder increasing the bioavailability of the invention can also be put in the form of capsules, stick packs (and remain in the form of powder), in sachets, in powder sprayers for nasal, buccal or vaginal route in powder sprayers. with special applicator, etc.
Pour obtenir un comprimé, il suffit d'ajouter un ou plusieurs diluants (par exemple : cellulose microcristalline, lactose, poudre de cellulose, phosphate dicalcique, saccharose, amidon, bicarbonate, mannitol...), lubrifiants (par exemple stéarate de magnésium, sodium stéaryl fumarate...), liants (par exemple : copolymère polyvinylpyπOlidone-vinyl acétate, povidone...), agent désintégrant ( amidon et dérivés, sodium glycolate amidon, alginate, cellulose microcristalline, croscarmellose sodium, crosspovidone...) ou autres excipients nécessaire à la réalisation de comprimés. Les comprimés peuvent être obtenus par compression directe, par granulation par voie humide, par granulation par voie sèche, ou toutes autres techniques connues par l'homme du métier.To obtain a tablet, simply add one or more diluents (for example: microcrystalline cellulose, lactose, cellulose powder, dicalcium phosphate, sucrose, starch, bicarbonate, mannitol ...), lubricants (for example magnesium stearate, sodium stearyl fumarate ...), binders (for example: polyvinylpyπOlidone-vinyl acetate, povidone ...), disintegrating agent (starch and derivatives, sodium glycolate starch, alginate, microcrystalline cellulose, croscarmellose sodium, crosspovidone ...) or other excipients necessary for the production of tablets. The tablets can be obtained by direct compression, by wet granulation, by dry granulation, or any other technique known to those skilled in the art.
Il est possible de faire des comprimés multi-couches ou double noyau, des comprimés enrobés (enrobages entériques, enrobage masquant le goût), des comprimés effervescents, des comprimés à résidence gastrique ou flottants...It is possible to make multi-layer or double core tablets, coated tablets (enteric coatings, coating masking the taste), effervescent tablets, gastric or floating tablets ...
Exemple 1_ réalisation comprimé à fease de progestérone à libération rapide.Example 1_ making rapid release progesterone fease tablet.
Solution saturée en principe actif, solution A :Solution saturated with active ingredient, solution A:
La solution à base d'huile de tournesol (Lesieur) est saturée en progestérone. Le ratio tensioactif/co-tensioactif est fixé à 75/25. On utilise un mélange de Tween® 80 (Seppic) et de Montane® 80 (Seppic). Le co-tensioactif est le Transcutol® (Gattefossé), il joue aussi le rôle de promoteur d'absorption et favorise le passage à travers la muqueuse.The sunflower oil solution (Lesieur) is saturated with progesterone. The surfactant / co-surfactant ratio is fixed at 75/25. A mixture of Tween ® 80 (Seppic) and Montane ® 80 (Seppic) is used. The co-surfactant is Transcutol ® (Gattefossé), it also plays the role of absorption promoter and promotes passage through the mucosa.
Figure imgf000022_0001
Figure imgf000022_0001
Pour cela, on mélange l'huile de tournesol, le Montane 80, Tween® 80, Transcutol® au moyen d'un agitateur Heidolph Bioblock RZR2051, à 500 t/min durant 6 minutes.For this, mix sunflower oil, Montane 80, Tween ® 80, Transcutol ® using a Heidolph Bioblock RZR2051 agitator, at 500 rpm for 6 minutes.
On obtient une phase translucide dans laquelle on incorpore la progestérone de manière à saturer le mélange. A température ambiante, sous agitation mécanique à l'agitateur Heidolph Bioblock RZR 2051 : 700 t/min durant 4 minutes , il est possible de passer la solution aux bain à ultra-sons quelques minutes (6 minutes 30 secondes) afin d'accélérer le processus de solubilisation du principe actif.A translucent phase is obtained in which progesterone is incorporated so as to saturate the mixture. At temperature ambient, with mechanical stirring with the Heidolph Bioblock RZR 2051 agitator: 700 rpm for 4 minutes, it is possible to pass the solution to the ultrasonic bath for a few minutes (6 minutes 30 seconds) in order to speed up the process of solubilization of the active ingredient.
Une fois le principe actif dissous, on ajoute l'eau. Le tout est homogénéisé à l'agitateur Heidolph Bioblock RZR2051 à 500t/min durant 5 minutes.Once the active ingredient has dissolved, water is added. The whole is homogenized with the Heidolph Bioblock RZR2051 agitator at 500 rpm for 5 minutes.
On obtient ainsi une solution A saturée en progestérone limpide, de couleur jaunâtre, transparente et liquide.This gives a solution A saturated with clear progesterone, yellowish in color, transparent and liquid.
Suspension en progestérone obtenue grâce à la solution A : suspension BProgesterone suspension obtained with solution A: suspension B
De la progestérone est ajouté à 62,5% en poids de la solution précédente, de manière à obtenir une suspension dosée à 40% en principe actif. Pour cela, la progestérone est ajoutée dans la solution A sous agitation mécanique avec l'agitateur Heidolph Bioblock RZR 2051, à 700 t/min durant 5 minutes.Progesterone is added to 62.5% by weight of the previous solution, so as to obtain a suspension dosed at 40% in active principle. For this, progesterone is added to solution A with mechanical stirring with the Heidolph Bioblock RZR 2051 agitator, at 700 rpm for 5 minutes.
Cette suspension B, qui est généralement une forme semi- solide crémeuse et opaque, a la composition suivante :This suspension B, which is generally a semi-solid creamy and opaque form, has the following composition:
Figure imgf000023_0001
Figure imgf000023_0001
Le mélange obtenu est une crème blanche, opaque et épaisse. Imprégnation de la suspension B sur un support inerte :The mixture obtained is a white, opaque and thick cream. Impregnation of suspension B on an inert support:
Une fois cette suspension B obtenue, elle est imprégnée sur de la silice tel que le Sipernat® 50 (Degussa). Pour cette manipulation, on utilise un mélangeur-granulateur-sécheur Zanchetta.Once this suspension B is obtained, it is impregnated on silica such as Sipernat ® 50 (Degussa). For this manipulation, a Zanchetta mixer-granulator-dryer is used.
Paramètres :Settings :
-vitesse de la pâle = 300 rpm-pale speed = 300 rpm
-Temps d'introduction de la suspension = 20 minutes-Time of introduction of the suspension = 20 minutes
-Temps d'homogénéisation = 7 minutes-Homogenization time = 7 minutes
La suspension B en progestérone est incorporée progressivement dans l'appareil pour être imprégnée sur la silice.The B progesterone suspension is gradually incorporated into the device to be impregnated on the silica.
La poudre imprégnée augmentant la biodisponibilité et/ou la solubilité a alors la composition suivante :The impregnated powder increasing the bioavailability and / or the solubility then has the following composition:
Figure imgf000024_0001
Figure imgf000024_0001
Profil de dissolution de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité ci-dessus comparée à une forme pharmaceutique commercialisée : l'Utrogestan ®100mg (Besins .Dissolution profile of the impregnated powder increasing the bioavailability and / or the solubility above compared to a pharmaceutical form marketed: Utrogestan ®100mg (Besins.
Le test de dissolution in vitro a été réalisé avec un dissolutest Sotax AT7, avec béchers de dissolution en verre. Le milieu de dissolution utilisé est du kleptose à 1%. La température du bain est maintenu à 37°C, et la vitesse de rotation des pâles est de 150 rpm. Le dosage est effectué en ligne par spectrométrie UV.The in vitro dissolution test was carried out with a Sotax AT7 dissolutest, with glass dissolution beakers. The dissolution medium used is 1% kleptose. The temperature of the bath is maintained at 37 ° C., and the speed of rotation of the blades is 150 rpm. The assay is carried out online by UV spectrometry.
Les résultats sont représentés graphiquement à la figure 5. La totalité de la dose est libérée en 1 heure avec la poudre imprégnée augmentant la biodisponibilité de l'invention alors que la formulation du commerce libère à peine plus de 50% en 6 heures.The results are shown graphically in Figure 5. The entire dose is released in 1 hour with the impregnated powder increasing the bioavailability of the invention while the commercial formulation releases just over 50% in 6 hours.
5 Caractérisation de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité de l'invention :5 Characterization of the impregnated powder increasing the bioavailability and / or the solubility of the invention:
Aptitude à P écoulementSuitability for flow
Ce test est effectué selon le test Pharmacopée Européenne 4.2 ; o 2.9.16This test is carried out according to the European Pharmacopoeia test 4.2; o 2.9.16
Masse de l'échantillon = 63,42 g Temps d'écoulement = infiniSample mass = 63.42 g Flow time = infinite
Volume apparent 5 Ce test est effectué selon le test Pharmacopée Européenne 4.2 ;Apparent volume 5 This test is carried out according to the European Pharmacopoeia test 4.2;
2.9.152.9.15
Masse échantillon = 64 gSample mass = 64 g
Volume apparent à V0 = 122 ml . Volume apparent à V10 = 114 ml o Volume apparent à V500 = 104 mlApparent volume at V0 = 122 ml. Apparent volume at V10 = 114 ml o Apparent volume at V500 = 104 ml
Aptitude au tassement = 10 mlCompacting ability = 10 ml
Mesure du taux d'humidité relativeRelative humidity measurement
Cette mesure est réalisée à l'aide d'un analyseur d'humidité MA 30 Sartorius 5 Paramètres : masse de l'échantillon=l,69g, Température=l 00°C Temps de dessiccation≈ 15min Résultat : Humidité relative= 9,70%This measurement is carried out using a MA 30 Sartorius 5 humidity analyzer Parameters: mass of the sample = 1.69 g, Temperature = l 00 ° C Drying time≈ 15 min Result: Relative humidity = 9.70 %
0 Granulométrie0 Grain size
Cette étude est réalisée à l'aide d'un granulometre laser Malvern Mastersizer 2000 équipé d'un vibreur Sirocco 2000 Paramètres : pression = 2 bars, 70% de vibration Granulométrie moyenne = 27,5 μm Réalisation des comprimésThis study is carried out using a Malvern Mastersizer 2000 laser granulometer equipped with a Sirocco 2000 vibrator Parameters: pressure = 2 bars, 70% vibration Average particle size = 27.5 μm Making the tablets
Le diluant utilisé est un mélange de Vivapur® 102 (Rettenmaïer) et d'Encompress® (Penwest).The diluent used is a mixture of Vivapur ® 102 (Rettenmaïer) and Encompress ® (Penwest).
Au mélangeur Turbula, les diluants et la poudre imprégnée sont mélangés durant 5 minutes. A l'aide d'une machine à comprimer alternative, avec des poinçons 11R11, on fabrique des comprimés comprenant 20% du mélange précédent.In the Turbula mixer, the diluents and the impregnated powder are mixed for 5 minutes. Using an alternative tableting machine, with 11R11 punches, tablets are produced comprising 20% of the above mixture.
La composition des comprimés est la suivante :The composition of the tablets is as follows:
Figure imgf000026_0001
Figure imgf000026_0001
Caractéristiques des comprimés -masse = 460 mg -dureté = 40 N -désagrégation = 20 secondesCharacteristics of the tablets - mass = 460 mg - hardness = 40 N - disintegration = 20 seconds
Exemple 2: réalisation d'une poudre imprégnée augmentant la biodisponibilité et/ou la solubilité à base de fénofibrate à libération rapide.Example 2: production of an impregnated powder increasing the bioavailability and / or the solubility based on quick-release fenofibrate.
La suspension Al est réalisée à base de Labrafac® CC (Gattefossé), de Montanox® 85 (Seppic), de propylène glycol (Copper), et d'eau distillée. Les 3 premiers composants sont mélangés à l'aide d'un agitateur Heidolph Bioblock RZR2051 à 700t/min.The suspension Al is performed based on DC Labrafac ® (Gattefosse), ® Montanox 85 (Seppic), propylene glycol (Copper), and distilled water. The first 3 components are mixed using a Heidolph Bioblock RZR2051 agitator at 700 rpm.
Puis, l'eau distillée est ajoutée, agitation mécanique à l'agitateur Heidolph Bioblock RZR2051 à 700t/min.Then, distilled water is added, mechanical stirring with the Heidolph Bioblock RZR2051 agitator at 700 rpm.
Le principe actif est ajouté au mélange précédent, la formulation est passée aux bains ultrasons durant 5 minutes. Puis agitation mécanique au Bioblock à 1200t/min durant 45 minutes. La formulation est la suivanteThe active ingredient is added to the previous mixture, the formulation is passed through ultrasonic baths for 5 minutes. Then mechanical agitation in the Bioblock at 1200 rpm for 45 minutes. The wording is as follows
Figure imgf000027_0001
Figure imgf000027_0001
On obtient une suspension blanche, assez épaisse.A fairly thick white suspension is obtained.
Imprégnation de la suspension Al chargée en fénofibrateImpregnation of the suspension Al loaded with fenofibrate
Une fois cette suspension obtenue, elle est imprégnée sur de la silice tel que du Sipernat® 50 (Degussa). Pour cette manipulation, on utilise d'un mélangeur-granulateur-sécheur Zanchetta. Paramètres :Once this suspension is obtained, it is impregnated on silica such as Sipernat ® 50 (Degussa). For this manipulation, a Zanchetta mixer-granulator-dryer is used. Settings :
-vitesse de la pâle = 300 rpm -Temps d'introduction de la suspension = 20 minutes -Temps d'homogénéisation = 7 minutes-pale speed = 300 rpm -Time of introduction of the suspension = 20 minutes -Homogenization time = 7 minutes
Figure imgf000027_0002
Figure imgf000027_0002
La formulation chargée en fénofibrate est incorporée progressivement dans l'appareil pour être imprégnée sur la silice.The formulation loaded with fenofibrate is gradually incorporated into the device to be impregnated on silica.
Profil de dissolution de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité ci-dessus comparée à une forme pharmaceutique commercialisée : Le lipanthyl®160mgDissolution profile of the impregnated powder increasing the bioavailability and / or the solubility above compared to a marketed pharmaceutical form: Lipanthyl ® 160mg
Le test de dissolution in vitro a été réalisé avec un dissolutest Sotax AT7, à palettes tournantes. Le milieu de dissolution utilisé est du SLS à O.IM. La température du bain est maintenu à 37°C, et la vitesse de rotation des pâles est de 75 rpm.The in vitro dissolution test was carried out with a Sotax AT7 dissolutest, with rotating paddles. The dissolution medium used is from SLS to O.IM. The temperature of the bath is maintained at 37 ° C., and the speed of rotation of the blades is 75 rpm.
Le dosage est effectué en ligne par spectrométrie UV. Les résultats sont représentés graphiquement à la figure 6. La poudre imprégnée augmentant la biodisponibilité et/ou la solubilité de l'invention permet de libérer de principe actif beaucoup plus rapidement que le Lipanthyl® 160mg durant les 10 premières minutes.The assay is carried out online by UV spectrometry. The results are shown graphically in Figure 6. The impregnated powder increasing the bioavailability and / or solubility of the invention permits release of active principle much more rapidly than Lipanthyl ® 160mg in the first 10 minutes.
Caracterisation de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité de l'invention :Characterization of the impregnated powder increasing the bioavailability and / or the solubility of the invention:
Aptitude à l'écoulementFlowability
Ce test est effectué selon le test Pharmacopée Européenne 4.2 ; 2.9.16 Masse de l'échantillon = 65,64 g Temps d'écoulement = infiniThis test is carried out according to the European Pharmacopoeia test 4.2; 2.9.16 Mass of the sample = 65.64 g Flow time = infinite
Volume apparentApparent volume
Ce test est effectué selon le test Pharmacopée Européenne 4.2 ; 2.9.15This test is carried out according to the European Pharmacopoeia test 4.2; 2.9.15
Masse échantillon = 65,64 gSample mass = 65.64 g
Volume apparent à VO = 154 mlApparent volume at VO = 154 ml
Volume apparent à V10 = 148 mlApparent volume at V10 = 148 ml
Volume apparent à V500 = 128 ml Volume apparent à V500 = 126 mlApparent volume at V500 = 128 ml Apparent volume at V500 = 126 ml
Aptitude au tassement = 20 mlCompaction capacity = 20 ml
Mesure du taux d'humidité relativeRelative humidity measurement
Cette mesure est réalisée à l'aide d'un analyseur d'humidité MA 30 Sartorius Paramètres : masse de Péchantillon= 1,002 g, Température=l 00°C Temps de dessiccation≈ 15min Résultat : Humidité relative= 5,69% GranulométrieThis measurement is carried out using a MA 30 Sartorius humidity analyzer Parameters: mass of the sample = 1.002 g, Temperature = l 00 ° C Drying time≈ 15 min Result: Relative humidity = 5.69% Granulometry
Cette étude est réalisée à l'aide d'un granulometre laser Malvern Mastersizer 2000 équipé d'un vibreur Sirocco 2000This study is carried out using a Malvern Mastersizer 2000 laser granulometer equipped with a Sirocco 2000 vibrator
Paramètres : pression = 2 bars, 70% de vibration Granulométrie moyenne = 20,89μmParameters: pressure = 2 bars, 70% vibration Average grain size = 20.89μm
Exemple 3^ réalisation cPune poudre imprégnée tentant la biodisponibilité et/ou la soin! a oase d9acydov!r à libération rapide. La suspension A2 est réalisée à base d'une solution aqueuse de HCl pH = 2, d'huile de soja raffinée (Sictia), de Tween® 80 (Fluka), de propylène glycol (Cooper). Les 3 derniers composants sont mélangés à l'aide d'un agitateur Heidolph Bioblock RZR2051 à 500t/min. Puis la solution aqueuse de HCl pH = 2 est ajoutée, sous agitation mécanique à l'agitateur Heidolph Bioblock RZR2051 à 700t/min.Example 3 ^ realization cAn impregnated powder attempting bioavailability and / or care! has a quick release 9 acydov! r case. The suspension A2 is produced on the basis of an aqueous solution of HCl pH = 2, refined soybean oil (Sictia), Tween® 80 (Fluka), propylene glycol (Cooper). The last 3 components are mixed using a Heidolph Bioblock RZR2051 agitator at 500 rpm. Then the aqueous HCl solution pH = 2 is added, with mechanical stirring to the Heidolph Bioblock RZR2051 agitator at 700 rpm.
Le principe actif est ajouté au mélange précédent, la formulation est passée aux bains ultrasons durant 5 minutes. Puis agitation mécanique au Bioblock à 900t/min durant 20 minutes. La formulation est la suivante :The active ingredient is added to the previous mixture, the formulation is passed through ultrasonic baths for 5 minutes. Then mechanical agitation in the Bioblock at 900 rpm for 20 minutes. The wording is as follows:
Figure imgf000029_0001
Figure imgf000029_0001
On obtient une suspension blanche, assez épaisse. Imprégnation de la suspension A2 chargée en ac clovirA fairly thick white suspension is obtained. Impregnation of suspension A2 charged with ac clovir
Une fois cette suspension obtenue, elle imprégnée sur de la silice tel que l'Aeroperl ®300 (Degussa). Pour cette manipulation utilisation d'un mélangeur-granulateur-sécheur Zanchetta. Paramètres :Once this suspension is obtained, it is impregnated on silica such as Aeroperl ®300 (Degussa). For this manipulation use of a Zanchetta mixer-granulator-dryer. Settings :
-vitesse de la pâle = 350 rpm-pale speed = 350 rpm
-Temps d'introduction de la suspension = 25 minutes-Time of introduction of the suspension = 25 minutes
-Temps d'homogénéisation ≈ 9 minutes-Homogenization time ≈ 9 minutes
La formulation chargée en acyclovir est incorporée progressivement dans l'appareil pour être imprégnée sur la silice.The formulation loaded with acyclovir is gradually incorporated into the apparatus to be impregnated on the silica.
La formulation de la poudre imprégnée augmentant la biodisponibilité et/ou la solubilité obtenue est la suivante :The formulation of the impregnated powder increasing the bioavailability and / or the solubility obtained is as follows:
Figure imgf000030_0001
Figure imgf000030_0001
Exemple 4 : réalisation de comprimé à base de progestérone à libération rapide.Example 4: Production of rapid release progesterone tablet.
Solution saturée en principe actif, solution A : La phase hydrophobe à base d'huile de tournesol (Lesieur) est saturée en progestérone. Le ratio tensioactif/co-tensio actif est fixé à 75/25. On utilise un mélange de tensioactif :Tween® 80 (Seppic) et Montane® 80 (Seppic). Le co-tensioactif est le Transcutol® (Gattefossé), il joue aussi le rôle de promoteur d'absorption et favorise le passage à travers la muqueuse gastro-intestinale.
Figure imgf000031_0001
Saturated solution of active ingredient, solution A: The hydrophobic phase based on sunflower oil (Lesieur) is saturated with progesterone. The surfactant / co-surfactant ratio is fixed at 75/25. A mixture of surfactants is used: Tween® 80 (Seppic) and Montane® 80 (Seppic). The co-surfactant is Transcutol® (Gattefossé), it also plays the role of promoter of absorption and promotes the passage through the gastrointestinal mucosa.
Figure imgf000031_0001
L'huile de Tournesol, le montane 80, le Tween 80 et le Transcutol sont mélangés au moyen d'un agitateur Heidolph Bioblock RZE2051 , à 500 tours/min durant 6 min, à température ambiante. On obtient un phase translucide dans laquelle on incorpore la progestérone jusqu'à saturation, sous agitation à 700 tours/min durant 4 min.Sunflower oil, montane 80, Tween 80 and Transcutol are mixed using a Heidolph Bioblock RZE2051 agitator, at 500 rpm for 6 min, at room temperature. A translucent phase is obtained in which the progesterone is incorporated until saturation, with stirring at 700 rpm for 4 min.
Une fois le principe actif dissous, la phase hydrophile (eau purifiée) est ajoutée. L'ensemble est homogénéisé à l'agitateur Heidolph Bioblock RZE2051 , à 500 tours/min durant 5 min.Once the active ingredient has dissolved, the hydrophilic phase (purified water) is added. The whole is homogenized with the Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min.
On obtient ainsi une solution A limpide saturée en Progestérone, de couleur jaunâtre, transparente et fluide.This gives a clear solution A saturated with progesterone, yellowish in color, transparent and fluid.
Suspension en Progestérone obtenue à partir de la solution A suspension BProgesterone suspension obtained from solution A suspension B
Figure imgf000031_0002
La progestérone est dispersée dans la solution A, jusqu'à l'obtention d'une suspension dosée à 45,28% en Progestérone, sous agitation à 700 tours/min durant 5 min à l'aide d'un agitateur Heidolph Bioblock RZR 2051. La suspension obtenue est légèrement visqueuse et blanche.
Figure imgf000031_0002
Progesterone is dispersed in solution A, until a suspension dosed at 45.28% in Progesterone is obtained, with stirring at 700 rpm for 5 min using a Heidolph Bioblock RZR 2051 agitator. The suspension obtained is slightly viscous and white.
Imprégnation de la suspension B sur un support inerteImpregnation of suspension B on an inert support
La suspension est adsorbée sur un support inerte telle que de la silice (Aeroperl® 300, Degussa).The suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
Figure imgf000032_0001
Figure imgf000032_0001
L'adsorption est réalisée à l'aide d'un mélangeur-granulateur Rotolab, Zancheta. Les paramètres d'imprégnation sont les suivants :Adsorption is carried out using a Rotolab mixer-granulator, Zancheta. The impregnation parameters are as follows:
-Vitesse de la tripâle = 300 RPM -Durée d'incorporation de la suspension = 20 s -Durée d'homogénéisation = 5 min -Speed of the triplet = 300 RPM -Duration of incorporation of the suspension = 20 s -Duration of homogenization = 5 min
Caracterisation de la poudre imprégnée à base de ProgestéroneCharacterization of the progesterone-based impregnated powder
Figure imgf000033_0001
Figure imgf000033_0001
Dissolution in vitro de la poudre imprégnée à base de ProgestéroneIn vitro dissolution of the progesterone-based impregnated powder
Le profil de dissolution de la poudre imprégnée à base de Progestérone améliorant la biodisponibilité et la solubilité est comparé à celui de la forme commerciale Utrogestran®.The dissolution profile of the progesterone-impregnated powder improving bioavailability and solubility is compared to that of the commercial form Utrogestran®.
Le test de dissolution est réalisé avec un dissolutest Sotax AT7, avec des cuves de dissolution en verre.The dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
Le milieu de dissolution utilisé est une solution de Kleptose à 1 %. La température du bain est maintenue à 37°C, la vitesse de rotation des pâles est de 150 RPM.The dissolution medium used is a 1% Kleptose solution. The temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 150 RPM.
Le dosage est réalisé en ligne par spectrophotométrie UV.The assay is carried out online by UV spectrophotometry.
Les résultats sont présentés sur la Figure 7, qui illustre une comparaison du profil de dissolution (Kleptose 1 %, 150 t/min) de la poudre imprégnée à base de progestérone dosée à 100 mg selon l'invention avec une formulation commerciale. Au bout d'1h, la totalité de la dose est libérée avec la poudre imprégnée alors que seule 10% de progestérone sont libérés à partir de la forme commerciale.The results are presented in FIG. 7, which illustrates a comparison of the dissolution profile (Kleptose 1%, 150 rpm) of the progesterone-based impregnated powder dosed at 100 mg according to the invention with a commercial formulation. After 1 hour, the entire dose is released with the impregnated powder while only 10% of progesterone is released from the commercial form.
Réalisation d© com rimés à partir de la poudre imprégné© deProduction of comrades from powder impregnated with
P oges érone La poudre imprégnée est mélangée avec un diluant (Vivapur® 12, JRS Pharma) et un désintégrant (Lycatab® C, Roquette) à l'aide d'un mélangeur Rotolab® (Zanchetta), à 150 RPM, durant 3min.P oges erone The impregnated powder is mixed with a diluent (Vivapur® 12, JRS Pharma) and a disintegrant (Lycatab® C, Roquette) using a Rotolab® mixer (Zanchetta), at 150 RPM, for 3 min.
Le mélange est ensuite comprimé avec une machine à comprimer alternative Frogerais.The mixture is then compressed with an alternative Frogerais tableting machine.
Figure imgf000034_0001
Dissolution in vitro des comprimés
Figure imgf000034_0001
In vitro dissolution of tablets
Le profil de dissolution des comprimés de Progestérone améliorant la biodisponibilité et la solubilité est comparée à celui de la forme commerciale Utrogestran®The dissolution profile of Progesterone tablets improving bioavailability and solubility is compared with that of the commercial form Utrogestran®
Le test de dissolution est réalisé avec un dissolutest Sotax AT7, avec des cuves de dissolution en verre.The dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
Le milieu de dissolution utilisé est une solution de Kleptose à 1 %. La température du bain est maintenue à 37°C, la vitesse de rotation des pâles est de 150 RPM.The dissolution medium used is a 1% Kleptose solution. The temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 150 RPM.
Le dosage est réalisé en ligne par spectrophotométrie UV.The assay is carried out online by UV spectrophotometry.
Les résultats sont présentés sur la Figure 8, qui illustre une comparaison du profil de dissolution (Kleptose 1%, 150 t/min, 37°C), entre respectivement, (i) une poudre imprégnée selon l'invention, (ii) un comprimé de poudre imprégnée selon l'invention et (iii), une formulation commerciale, dosée à 100 mg de progestérone.The results are presented in FIG. 8, which illustrates a comparison of the dissolution profile (Kleptose 1%, 150 rpm, 37 ° C), between, respectively, (i) a powder impregnated according to the invention, (ii) a powder tablet impregnated according to the invention and (iii), a commercial formulation, dosed at 100 mg of progesterone.
Au bout de 60 min, les comprimés à base de la poudre imprégnée libèrent environ 95% de la Progestérone tandis seulement 10% de progestérone sont libérés de la forme commerciale.After 60 min, the tablets based on the impregnated powder release approximately 95% of progesterone while only 10% of progesterone are released from the commercial form.
Les résultats d'analyse de la granulométrie de la poudre imprégnée à base de progestérone sont présentés sur la Figure 9, qui illustre la distribution de la taille des particules de cette poudre.The results of analysis of the granulometry of the powder impregnated with progesterone are presented in FIG. 9, which illustrates the distribution of the particle size of this powder.
Exemple 5 : Réalisation d'un comprimé à base dAcyclovir à libération rapideEXAMPLE 5 Production of a Rapid-Release Acyclovir-Based Tablet
Suspension d'Acyclovir L'Acyclovir est solubilisé dans la phase hydrophile (Tampon HCl, pH 2), à 500 tours/min durant 10 min, à température ambiante. La solution A obtenue est limpide et fluide.Suspension of Acyclovir Acyclovir is dissolved in the hydrophilic phase (HCl buffer, pH 2), at 500 rpm for 10 min, at room temperature. Solution A obtained is clear and fluid.
La phase hydrophobe (Captex® 300, Abitec), le tensioactif (Acconon® CC6, Abitec) et le co-tensioactif (Plural oléique, Gattefossé) sont mélangés durant 5min, à 500 RPM, à température ambiante. La solution B obtenue est légèrement jaunâtre et fluide.The hydrophobic phase (Captex® 300, Abitec), the surfactant (Acconon® CC6, Abitec) and the co-surfactant (Plural oleic, Gattefossé) are mixed for 5 min, at 500 RPM, at room temperature. Solution B obtained is slightly yellowish and fluid.
La solution A suturée en Acyclovir et la solution B sont mélangées, 5 min 500 tours/min.Solution A sutured in Acyclovir and solution B are mixed, 5 min 500 rpm.
La mélange C obtenu est fluide et légèrement jaunâtre.The mixture C obtained is fluid and slightly yellowish.
Le restant de PAcyclovir est mise en suspension, sous agitation 700RPM, durant10min,.The remainder of PAcyclovir is suspended, with stirring 700RPM, for 10 min.
La suspension D obtenue à 65% d'Acyclovir est blanche et crémeuse.Suspension D obtained at 65% Acyclovir is white and creamy.
Ces essais sont réalisés avec un agitateur Heidolph Bioblock RZE2051.These tests are carried out with a Heidolph Bioblock RZE2051 agitator.
Figure imgf000036_0001
Figure imgf000036_0001
Imprégnation de la suspension D sur un support inerteImpregnation of suspension D on an inert support
La suspension est adsorbée sur un support inerte telle que de la silice (Aeroperl® 300, Degussa).The suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
L'adsorption est réalisée à l'aide d'un mélangeur-granulateur Rotolab, Zanchetta.Adsorption is carried out using a Rotolab mixer-granulator, Zanchetta.
Les paramètres d'imprégnation sont les suivants : -Vitesse de la tripâle = 250 RPM -Durées d'incorporation de la suspension = 20 s -Durée d'homogénéisation = 5 min.
Figure imgf000037_0001
The impregnation parameters are as follows: -Speed of the triple blade = 250 RPM -Duration of incorporation of the suspension = 20 s -Homogenization time = 5 min.
Figure imgf000037_0001
Caracterisation de la poudre imprégnée à base d'AcyclovirCharacterization of the powder impregnated with Acyclovir
Figure imgf000037_0002
Figure imgf000037_0002
Dissolution in vitro de la poudre imprégnée à base d'AcyclovirIn vitro dissolution of the powder impregnated with Acyclovir
Le profil de dissolution de la poudre imprégnée à base d'Acyclovir améliorant la biodisponibilité et la solubilité est comparée à celui de la forme commerciale Zovirax®. Le test de dissolution est réalisé avec un dissolutest Sotax AT7, avec des cuves de dissolution en verre.The dissolution profile of the impregnated powder based on Acyclovir improving the bioavailability and the solubility is compared with that of the commercial form Zovirax®. The dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
Le milieu de dissolution utilisé est une solution de HCl 0,01 N.The dissolution medium used is a 0.01 N HCl solution.
La température du bain est maintenue à 37°C, la vitesse de rotation des pâles est de 100 RPM.The temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.
Le dosage est réalisé en ligne par specfrophotométrie UV.The assay is carried out online by UV specfrophotometry.
Les résultats comparatifs de profil de dissolution sont représentés sur la Figure 10, qui illustre une comparaison du profil de dissolutionComparative dissolution profile results are shown in Figure 10, which illustrates a comparison of the dissolution profile
(milieu HCl 0,01 N ; 100 t/min ; 37°C) d'une poudre imprégnée à base d'Acyclovir selon l'invention avec une formulation d'Acyclovir commerciale, dosées à 200 mg.(0.01 N HCl medium; 100 rpm; 37 ° C.) of an impregnated powder based on Acyclovir according to the invention with a commercial Acyclovir formulation, dosed at 200 mg.
100% de la dose est libérée en moins de 2 min avec la poudre imprégnée100% of the dose is released in less than 2 min with the impregnated powder
Au bout de 2 min la forme commerciale ne libère que 55% d'Acyclovir.After 2 min the commercial form releases only 55% of Acyclovir.
Réalisation de comprimés à partir de la poudre imprégnée d'AcyclovirProduction of tablets from the powder impregnated with Acyclovir
La poudre imprégnée est mélangée avec un diluant (Vivapur® 12,The impregnated powder is mixed with a diluent (Vivapur® 12,
JRS Pharma) et un désintégrant (Lycatab® C, Roquette) à l'aide d'un mélangeur Rotolab® (Zanchetta), à 150 RPM, durant 3 min.JRS Pharma) and a disintegrant (Lycatab® C, Roquette) using a Rotolab® mixer (Zanchetta), at 150 RPM, for 3 min.
Le mélange est ensuite comprimé avec une machine à comprimer alternative Frogerais. The mixture is then compressed with an alternative Frogerais tableting machine.
Figure imgf000039_0001
Figure imgf000039_0001
Dissolution in vitro des comprimés à base de poudre imprégnéeIn vitro dissolution of tablets based on impregnated powder
Le profil de dissolution des comprimés à base de poudre imprégnée améliorant la biodisponibilité et la solubilité est comparé à celui de la forme commerciale Zovirax®.The dissolution profile of tablets based on impregnated powder improving bioavailability and solubility is compared with that of the commercial form Zovirax®.
Le test de dissolution est réalisé avec un dissolutest Sotax AT7, avec des cuves de dissolution en verre.The dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks.
Le milieu de dissolution utilisé est une solution de HCl 0,01 N.The dissolution medium used is a 0.01 N HCl solution.
La température du bain est maintenue à 37°C, la vitesse de rotation des pâles est de 100 RPM. Le dosage est réalisé en ligne par spectrophotométrie UV.The temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM. The assay is carried out online by UV spectrophotometry.
Les résultats de profil de dissolution sont représentés sur la Figure 11 qui illustre une comparaison des profils de dissolution (HCl 0,0 IN ; 100 t/min.) (i) d'une poudre imprégnée à base d'Acyclovir selon l'invention, (ii) d'un comprimé fabriqué à partir de cette poudre imprégnée et (iii) d'une formulation commerciale dénommée ZOVIRAX® dosée à 200 mg.The dissolution profile results are represented in FIG. 11 which illustrates a comparison of the dissolution profiles (HCl 0.0 IN; 100 rpm) (i) of an impregnated powder based on Acyclovir according to the invention , (ii) a tablet made from this impregnated powder and (iii) a commercial formulation called ZOVIRAX® dosed at 200 mg.
Les résultats d'analyse de granulométrie de la poudre fîlmogène imprégnée à base d'Acyclovir sont représentés sur la Figure 12 qui illustre la courbe de distribution de taille des particules de cette poudre.The results of particle size analysis of the film-forming powder impregnated with Acyclovir are represented in FIG. 12 which illustrates the curve of distribution of size of the particles of this powder.
Exemple 6 : Réalisation d'un comprimé à base de Fénofibrate co- micronisé avec du sodium lauryl sulfate à libération rapideEXAMPLE 6 Production of a Fenofibrate-Based Co-Micronized Tablet with Rapid-Release Sodium Lauryl Sulfate
Le Capryol® 90 (Gattefossé), l'Acconon® CC6 (Abitec), le Transcutol® (Gattefossé) sont mélangés au moyen d'un agitateur Heidolph Bioblock RZE2051 , à 500 tours/min durant 5 min, à température ambiante.Capryol® 90 (Gattefossé), Acconon® CC6 (Abitec), Transcutol® (Gattefossé) are mixed using a Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min at room temperature.
On obtient un phase translucide dans laquelle on incorpore le Fénofibrate co-micronisé jusqu'à saturation, sous agitation à 700 tours/min durant 10 min.A translucent phase is obtained in which the co-micronized fenofibrate is incorporated until saturation, with stirring at 700 rpm for 10 min.
Une fois le principe actif dissous, la phase hydrophile (eau purifiée) est ajoutée. L'ensemble est homogénéisé à l'agitateur Heidolph Bioblock RZE2051 , à 500 tours/min durant 5 min.Once the active ingredient has dissolved, the hydrophilic phase (purified water) is added. The whole is homogenized with the Heidolph Bioblock RZE2051 agitator, at 500 rpm for 5 min.
On obtient ainsi une solution A limpide saturée en Fénofibrate co- micronisé, de couleur jaunâtre, transparente et fluide.A clear solution A saturated with co-micronized fenofibrate, of yellowish color, transparent and fluid, is thus obtained.
Le restant du Fénofibrate co-micronisé est dispersée dans la solution A, jusqu'à l'obtention d'une suspension dosée à 41 ,52% en Fénofibrate co- micronisé, sous agitation à 700 tours/min durant 10 min à l'aide d'un agitateur Heidolph Bioblock RZR 2051.The remainder of the co-micronized Fenofibrate is dispersed in solution A, until a suspension containing 41.52% of co-micronized Fenofibrate is obtained, with stirring at 700 rpm for 10 min using a Heidolph Bioblock RZR 2051 agitator.
La suspension B obtenue est visqueuse et blanche.
Figure imgf000041_0001
The suspension B obtained is viscous and white.
Figure imgf000041_0001
Imprégnation de la suspension B sur un support inerteImpregnation of suspension B on an inert support
La suspension est adsorbée sur un support inerte telle que de la silice (Aeroperl® 300, Degussa).The suspension is adsorbed on an inert support such as silica (Aeroperl® 300, Degussa).
L'adsorption est réalisée à l'aide d'un mélangeur-granulateur Rotolab, Zanchetta.Adsorption is carried out using a Rotolab mixer-granulator, Zanchetta.
Les paramètres d'imprégnation sont les suivants : -Vitesse de la tripâle = 300 RPM -Durée d'incorporation de la suspension = 20 s -Durée d'homogénéisation = 5 min The impregnation parameters are as follows: -Speed of the triple blade = 300 RPM -Duration of incorporation of the suspension = 20 s -Duration of homogenization = 5 min
Figure imgf000042_0001
Figure imgf000042_0001
Dissolution in vitro de la poudre imprégnée à base de Fénofibrate co-micronisé Le profil de dissolution de la poudre imprégnée à base deIn vitro dissolution of the impregnated powder based on co-micronized Fenofibrate The dissolution profile of the impregnated powder based on
Fénofibrate co-micronisé améliorant la biodisponibilité et la solubilité est comparé à celui de la forme commerciale Lipanthyl.Co-micronized fenofibrate improving bioavailability and solubility is compared to that of the commercial form Lipanthyl.
Le test de dissolution est réalisé avec un dissolutest Sotax AT7, avec des cuves de dissolution en verre. Le milieu de dissolution utilisé est une solution de sodium lauryl sulfate à 0,1 M.The dissolution test is carried out with a Sotax AT7 dissolutest, with glass dissolution tanks. The dissolution medium used is a 0.1 M sodium lauryl sulfate solution.
La température du bain est maintenue à 37°C, la vitesse de rotation des pâles est de 100 RPM.The temperature of the bath is maintained at 37 ° C., the speed of rotation of the blades is 100 RPM.
Le dosage est réalisé en ligne par spectrophotométrie UV. Les résultats de profil de dissolution in vitro sont représentés sur la Figure 13, qui illustre une comparaison des profils de dissolution (SLS.The assay is carried out online by UV spectrophotometry. The in vitro dissolution profile results are shown in Figure 13, which illustrates a comparison of dissolution profiles (SLS.
0,1 M ; 100 t/min.) d'une poudre imprégnée selon l'invention à base de fénofibrate et d'une formulation commerciale dénommée LIPANTHYL®, dosée à 160 mg. La libération du Fénofibrate est plus rapide au cours des 6 premières minutes avec la poudre imprégnée qu'avec la forme commerciale. 0.1 M; 100 rpm) of an impregnated powder according to the invention based on fenofibrate and of a commercial formulation called LIPANTHYL®, dosed at 160 mg. The release of Fenofibrate is faster during the first 6 minutes with the impregnated powder than with the commercial form.

Claims

REVENDICATIONS
1. Poudre imprégnée augmentant la biodisponibilité et/ou la solubilité d'au moins un principe actif comprenant un support solide, inerte, sous forme particulaire imprégné par un milieu liquide comprenant une phase hydrophobe et une phase hydrophile, au moins un tensioactif et au moins un principe actif, caractérisée en ce que le(s) principe(s) actif(s) est (sont) dissous dans l'une desdites phases hydrophile ou hydrophobe et sous forme de suspension dans l'autre desdites phases.1. Impregnated powder increasing the bioavailability and / or the solubility of at least one active principle comprising a solid, inert support, in particulate form impregnated with a liquid medium comprising a hydrophobic phase and a hydrophilic phase, at least one surfactant and at least an active principle, characterized in that the active principle (s) is (are) dissolved in one of said hydrophilic or hydrophobic phases and in the form of a suspension in the other of said phases.
2. Poudre imprégnée selon la revendication 1, caractérisée en ce que le milieu liquide comprend en outre au moins un co- tensioactif.2. An impregnated powder according to claim 1, characterized in that the liquid medium also comprises at least one co-surfactant.
3. Poudre imprégnée selon la revendication 1 ou 2, caractérisée en ce que le (ou les) co-tensioactif(s) est (sont) choisi(s) parmi les alcools, les éthers de glycol, le glycol et ses dérivés, le propylène glycol et ses dérivés, les esters lauriques du propylène glycol, le polyglycérol et ses dérivés, les esters oléiques du polyglycérol et l'éthyldiglycol. 3. Impregnated powder according to claim 1 or 2, characterized in that the (or) co-surfactant (s) is (are) chosen (s) from alcohols, glycol ethers, glycol and its derivatives, propylene glycol and its derivatives, lauric esters of propylene glycol, polyglycerol and its derivatives, oleic esters of polyglycerol and ethyldiglycol.
4. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le (ou les) tensioactif(s) est (sont) choisi(s) parmi les tensioactifs non-ioniques, anioniques, cationiques et amphiphiles.4. Powder impregnated according to any one of the preceding claims, characterized in that the (or) surfactant (s) is (are) chosen (s) from nonionic, anionic, cationic and amphiphilic surfactants.
5. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le (ou les) tensioactif(s) représentent) au moins 1%, de préférence 2 à 70%, et mieux 10 à 60% en poids de la microémulsion liquide.5. An impregnated powder according to any one of the preceding claims, characterized in that the surfactant (s) represent (s) at least 1%, preferably 2 to 70%, and better still 10 to 60% by weight of the liquid microemulsion.
6. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que la phase hydrophobe du milieu liquide est choisie parmi les huiles végétales, minérales, animales ou synthétiques, les mono-, di et/ou triglycérides, les alcools gras et leurs dérivés, les esters de polyols, la paraffine liquide, les hydrocarbures à longue chaîne, le tocophérol et ses dérivés, les acides gras aliphatiques, les esters d'acides gras, les huiles de silicones, les composés phospholipidiques et leurs dérivés, et les mélanges de ces composés.6. Powder impregnated according to any one of the preceding claims, characterized in that the hydrophobic phase of the liquid medium is chosen from vegetable, mineral, animal or synthetic oils, mono-, di and / or triglycerides, fatty alcohols and their derivatives, polyol esters, liquid paraffin, long chain hydrocarbons, tocopherol and its derivatives, aliphatic fatty acids, fatty acid esters, silicone oils, phospholipid compounds and their derivatives, and mixtures of these compounds.
7. Poudre imprégnée selon l'une quelconque des revendications ' précédentes, caractérisée en ce que la phase 5 hydrophile du milieu liquide est choisie parmi l'eau, les mélanges hydroalcooliques, les solutions aqueuses salines, les solutions aqueuses tamponnées, les mélanges eau-polyéthylène glycol, les mélanges eau-glycérol, les solutions aqueuses de glucose et les mélanges eau-propylène glycol. o7. Impregnated powder according to any one of the preceding claims, characterized in that the hydrophilic phase of the liquid medium is chosen from water, hydroalcoholic mixtures, aqueous saline solutions, aqueous buffered solutions, water mixtures- polyethylene glycol, water-glycerol mixtures, aqueous glucose solutions and water-propylene glycol mixtures. o
8. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que la (ou les) matière(s) active(s) est (sont) choisie(s) parmi les matières actives hydrosolubles, liposolubles et amphiphiles.8. Powder impregnated according to any one of the preceding claims, characterized in that the (or) active material (s) is (are) chosen (s) from the water-soluble, liposoluble and amphiphilic active materials.
9. Poudre imprégnée sèche selon l'une quelconque des 5 revendications précédentes, caractérisée en ce que la (ou les) matière(s) active(s) est (sont) choisie(s) parmi celles utilisées dans les domaines pharmaceutique, parapharmaceutique, cosmétique, des compléments alimentaires et agroalimentaire.9. Dry impregnated powder according to any one of the preceding claims, characterized in that the active material (s) is (are) chosen from those used in the pharmaceutical, parapharmaceutical fields, cosmetics, food and agri-food supplements.
10. Poudre imprégnée selon la revendication 9, caractérisée en 0 ce que la (ou les) matière(s) active(s) est (sont) choisie(s) parmi celles utilisées dans les familles pharmacothérapeutiques suivantes : allergologie, anesthésie / réanimation, cancérologie et hématologie, cardiologie et angiologie, contraception et interruption de grossesse, dermatologie, endocrinologie, gastroentéropathologie, gynécologie, 5 immunologie, infectiologie, métabolisme et nutrition, neurologie / psychiatrie, ophtalmologie, oto-rhino-laryngologie, pneumologie, rhumatologie, stomatologie, toxicologie, urologie / néphrologie, ainsi que parmi les antalgiques et antispasmodiques, antiinflammatoires, les produits de contraste utilisés en radiologie, les o hémostatiques et les produits de traitement du sang et dérivés.10. Impregnated powder according to claim 9, characterized in that the active material (s) is (are) chosen from those used in the following pharmacotherapeutic families: allergology, anesthesia / resuscitation, oncology and hematology, cardiology and angiology, contraception and termination of pregnancy, dermatology, endocrinology, gastroenteropathology, gynecology, 5 immunology, infectiology, metabolism and nutrition, neurology / psychiatry, ophthalmology, otolaryngology, pneumology, rheumatology, stomatology, toxicology , urology / nephrology, as well as analgesics and antispasmodics, anti-inflammatories, contrast agents used in radiology, o hemostats and blood treatment products and derivatives.
11. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le milieu liquide contient de 0,001 à 70% en poids, de préférence 0,5 à 60% en poids de matière active par rapport au poids total du système liquide. 11. Powder impregnated according to any one of the preceding claims, characterized in that the liquid medium contains from 0.001 to 70% by weight, preferably 0.5 to 60% by weight of active material relative to the total weight of the liquid system .
12. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le milieu liquide comprend en outre au moins un agent adhésif.12. Impregnated powder according to any one of the preceding claims, characterized in that the liquid medium also comprises at least one adhesive agent.
13. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le milieu liquide comprend en outre au moins un adjuvant de pénétration.13. Powder impregnated according to any one of the preceding claims, characterized in that the liquid medium further comprises at least one penetration adjuvant.
14. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le milieu liquide comprend en outre au moins un polymère thermoréversible. 14. Impregnated powder according to any one of the preceding claims, characterized in that the liquid medium also comprises at least one thermoreversible polymer.
15. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le milieu liquide représente 1 à 99%, de préférence 20 à 90%, mieux 40 à 90%, et mieux encore 50 à 80% du poids total de la «poudre imprégnée».15. Powder impregnated according to any one of the preceding claims, characterized in that the liquid medium represents 1 to 99%, preferably 20 to 90%, better 40 to 90%, and better still 50 to 80% of the total weight of the "impregnated powder".
16. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que le support solide inerte est choisi parmi les silices naturelles, les gels de silice, les silices fumées, les silices précipitées, les argiles, le talc, l'hydroxyde de magnésium, l'hydroxyde d'aluminium, l'oxyde de magnésium, les maltodextrines, les cyclodextrines, des dérivés cellulosiques et leurs mélanges.16. Impregnated powder according to any one of the preceding claims, characterized in that the inert solid support is chosen from natural silicas, silica gels, fumed silicas, precipitated silicas, clays, talc, hydroxide magnesium, aluminum hydroxide, magnesium oxide, maltodextrins, cyclodextrins, cellulose derivatives and mixtures thereof.
17. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce que la phase dans laquelle est (sont) dissous le (les) principe(s) actif(s) constitue une solution saturée en principe(s) actif(s). 17. Powder impregnated according to any one of the preceding claims, characterized in that the phase in which is (are) dissolved the (the) active ingredient (s) constitutes a saturated solution of active ingredient (s) ).
18. Poudre imprégnée selon l'une quelconque des revendications précédentes, caractérisée en ce qu'elle comprend un ou plusieurs adjuvants choisis parmi les arômes, les parfums, les huiles essentielles, les colorants, les antioxydants, les conservateurs, les édulcorants et les charges. 18. Powder impregnated according to any one of the preceding claims, characterized in that it comprises one or more adjuvants chosen from aromas, perfumes, essential oils, colors, antioxidants, preservatives, sweeteners and fillers .
19. Procédé de fabrication d'une «poudre imprégnée », caractérisé en ce qu'il comprend :19. Method for manufacturing an "impregnated powder", characterized in that it comprises:
- l'obtention d'un milieu liquide comprenant une phase hydrophile et une phase hydrophobe, au moins un tensioactif et au moins un principe actif dissous dans au moins une desdites phases et présent dans l'autre desdites phases sous forme d'une suspension ;obtaining a liquid medium comprising a hydrophilic phase and a hydrophobic phase, at least one surfactant and at least one active principle dissolved in at least one of said phases, and present in the other of said phases in the form of a suspension;
- le mélange d'une quantité appropriée du milieu liquide et d'une quantité appropriée d'un support solide inerte sous forme particulaire capable d' adsorber le milieu liquide ; et- Mixing an appropriate amount of the liquid medium and an appropriate amount of an inert solid support in particulate form capable of adsorbing the liquid medium; and
- la récupération d'une « poudre imprégnée ».- recovery of an "impregnated powder".
20. Procédé selon la revendication 19, caractérisé en ce que le milieu liquide est obtenu en solubilisant une quantité de principe(s) actif(s) dans une desdites phases, mélangeant à la phase contenant le(s) principe(s) actif(s) dissous l'autre desdites phases, ajoutant une quantité supplémentaire de principe(s) actif(s) au mélange des deux phases pour former une suspension dans au moins l'autre desdites phases.20. The method of claim 19, characterized in that the liquid medium is obtained by solubilizing an amount of active principle (s) in one of said phases, mixing with the phase containing the active principle (s) ( s) dissolved the other of said phases, adding an additional quantity of active principle (s) to the mixture of the two phases to form a suspension in at least the other of said phases.
21. Procédé selon la revendication 19, caractérisé en ce que le milieu liquide est obtenu en mélangeant les deux phases et en ajoutant une quantité de principe(s) actif(s) suffisante pour obtenir une dissolution du (des) principe(s) actif(s) dans au moins l'une des phases et une suspension du (des) principe(s) actif(s) dans au moins l'autre des phases. 21. Method according to claim 19, characterized in that the liquid medium is obtained by mixing the two phases and by adding a quantity of active principle (s) sufficient to obtain a dissolution of the active principle (s) (s) in at least one of the phases and a suspension of the active principle (s) in at least the other of the phases.
22. Poudre imprégnée selon l'une quelconque des revendications 1 à 18, caractérisée en ce qu'elle se présente dans un conditionnement adapté à l'administration de toute ou partie de cette poudre imprégnée connue de l'homme du métier.22. Impregnated powder according to any one of claims 1 to 18, characterized in that it is presented in a packaging suitable for the administration of all or part of this impregnated powder known to those skilled in the art.
23. Poudre imprégnée selon l'une quelconque des revendications 1 à 18, caractérisée en ce que toute ou partie de cette23. Impregnated powder according to any one of claims 1 to 18, characterized in that all or part of this
« poudre imprégnée » est présentée sous forme de sachet, stick-pack, lingette, gélule, dans un flacon, pressurisée ou non, ou dans un pulvérisateur de poudre par voie nasale, buccale ou vaginale."Impregnated powder" is presented in the form of a sachet, stick-pack, wipe, capsule, in a bottle, pressurized or not, or in a powder sprayer by nasal, oral or vaginal route.
24. Poudre imprégnée selon l'une quelconque des revendications 1 à 18, caractérisée en ce que toute ou partie de cette24. Powder impregnated according to any one of claims 1 to 18, characterized in that all or part of this
« poudre imprégnée » est mise sous forme de comprimés nus ou pellicules, des comprimés dragéifiés des comprimés enrobés (enrobage soluble, enrobage pH-dépendant ou indépendant, à libération gastrique, intestinale ou autre), des comprimés matriciels, des comprimés osmotiques, des comprimés multicouches, des comprimés effervescents, des comprimés double noyau, des comprimés flottants, des formes à résidence gastrique et/ou flottante, des formes mucoadhésives, des gélules, des poudres, des formes multiparticulaires telles que des granules, microgranules enrobées (dragéifiées, à enrobage soluble, pH-dépendant) ou non, mucoadhésives, des pulvérisats solides."Impregnated powder" is put into the form of bare tablets or films, coated tablets coated tablets (soluble coating, pH-dependent or independent coating, gastric, intestinal or other release), matrix tablets, osmotic tablets, tablets multilayer, effervescent tablets, double-core tablets, floating tablets, gastric and / or floating forms, mucoadhesive forms, capsules, powders, multiparticulate forms such as granules, coated microgranules (coated, soluble coating, pH -dependent) or not, mucoadhesive, solid sprays.
25. Poudre imprégnée selon l'une quelconque des revendications 1 à 18 et 22 à 24, caractérisée en ce qu'elle se trouve sous une forme galénique dont le profil de libération est choisi parmi la libération immédiate, modifiée, retardée, bimodale ou puisée.25. Impregnated powder according to any one of claims 1 to 18 and 22 to 24, characterized in that it is in a galenical form the release profile of which is chosen from immediate, modified, delayed, bimodal or pulsed release. .
26. Utilisation de la « poudre imprégnée » selon l'une quelconque des revendications 1 à 18, pour la fabrication de comprimés nus ou pellicules, de comprimés dragéifiés, de comprimés enrobés (enrobage soluble, enrobage pH-dépendant ou indépendant à libération gastrique, intestinale ou autre), de comprimés matriciels, de comprimés osmotiques, de comprimés multicouches, de comprimés effervescents, de comprimés double noyau, de comprimés flottants, de formes à résidence gastrique et/ou flottantes, de formes mucoadhésives, de gélules, de poudres, de formes multiparticulaires telles que des granules, microgranules enrobées (dragéifiées, à enrobage soluble, pH-dépendant) ou non, mucoadhésives et des pulvérisats solides. 26. Use of the “impregnated powder” according to any one of claims 1 to 18, for the manufacture of bare tablets or films, coated tablets, coated tablets (soluble coating, pH-dependent or independent gastric release coating, intestinal or other), matrix tablets, osmotic tablets, multilayer tablets, effervescent tablets, double-core tablets, floating tablets, gastric and / or floating forms, mucoadhesive forms, capsules, powders, multiparticulate forms such as granules, coated microgranules (coated, soluble coating, pH-dependent) or not, mucoadhesive and solid sprays.
PCT/FR2004/000541 2003-03-06 2004-03-05 Impregnated powder improving bioavailability and/or solubility and method of production WO2004080381A2 (en)

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MXPA05009440A MXPA05009440A (en) 2003-03-06 2004-03-05 Impregnated powder improving bioavailability and/or solubility and method of production.
AU2004218859A AU2004218859B2 (en) 2003-03-06 2004-03-05 Impregnated powder improving bioavailability and/or solubility and method of production
US10/547,797 US7569274B2 (en) 2003-03-06 2004-03-05 Impregnated powder improving bioavailability and/or solubility and method of production
BRPI0408065-3A BRPI0408065A (en) 2003-03-06 2004-03-05 impregnated powder, its manufacturing process and its use
JP2006505704A JP4901469B2 (en) 2003-03-06 2004-03-05 Impregnated powder for increasing bioavailability and / or solubility and method for producing the same
EP04717669A EP1603538A2 (en) 2003-03-06 2004-03-05 Impregnated powder improving bioavailability and/or solubility and method of production
CA2518200A CA2518200C (en) 2003-03-06 2004-03-05 Impregnated powder improving bioavailability and/or solubility and method of production
NO20054562A NO20054562L (en) 2003-03-06 2005-10-04 Impregnated powder which improves bioavailability and / or solubility and process of preparation thereof

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EP1603538A2 (en) 2005-12-14
US20060182691A1 (en) 2006-08-17
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JP4901469B2 (en) 2012-03-21
CA2518200A1 (en) 2004-09-23
CA2518200C (en) 2013-04-30
MXPA05009440A (en) 2006-04-07
JP2006519820A (en) 2006-08-31
AU2004218859A1 (en) 2004-09-23
RU2367412C2 (en) 2009-09-20
NO20054562D0 (en) 2005-10-04
AU2004218859B2 (en) 2009-10-15
FR2851918B1 (en) 2006-06-16
FR2851918A1 (en) 2004-09-10
RU2005130989A (en) 2006-08-10
BRPI0408065A (en) 2006-02-14
WO2004080381A3 (en) 2005-07-28

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